Advanced Solid Tumors, Metastatic Melanoma
Conditions
Keywords
solid tumor, melanoma
Brief summary
This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.
Interventions
DRUGlosartan
taken orally
DRUGdextromethorphan
taken orally
DRUGcaffeine
taken orally
DRUGomeprazole
taken orally
DRUGmidazolam
taken orally
DRUGrosuvastatin
taken orally
DRUGbupropion immediate release (IR)
taken orally
DRUGencorafenib
taken orally
DRUGbinimetinib
taken orally
DRUGmodafinil
taken orally
Sponsors
Pierre Fabre Laboratories
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: * Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors * Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; * Evidence of measurable or non-measurable lesions * Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry * Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 * Adequate bone marrow, hepatic and renal function as specified in the protocol * ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. Key
Exclusion criteria
- Patients meeting any of the following criteria are not eligible for enrollment in the study: * Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\] demonstrating no current evidence of progressive brain metastases at screening); * Symptomatic or untreated leptomeningeal disease; * History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); * Clinically significant cardiac disease * Known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden syndrome); * Thromboembolic event except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment. * Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; * ARM 1 ONLY: Positive urine cotinine test at screening * ARM 3 ONLY: * History of psychosis, depression or mania; * History of angioedema; * History of mitral valve prolapse; * History of left ventricular hypertrophy;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine. |
| Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole. |
| Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion. |
| Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine. |
| AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole. |
| AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion. |
| The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. |
| Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan. |
| Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. |
| Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan. |
| Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. |
| AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. |
| AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. |
| AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole. |
| Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. |
| Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. |
| Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole. |
| Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole. |
| T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). |
| CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). |
| Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. |
| Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. |
| Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 | Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. |
| Fe for E-3174 on Day -7, Day 1 and Day 14 | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan. |
| Fe for Dextromethorphan on Day -7, Day 1 and Day 14 | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. |
| Fe for Dextrorphan on Day -7, Day 1 and Day 14 | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan. |
| Cmax of Encorafenib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of LHY746 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. |
| Cmax of Binimetinib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of AR00426032 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. |
| AUClast of Encorafenib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of LHY746 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib. |
| AUClast of Binimetinib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of AR00426032 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. AR00426032 was the metabolite of binimetinib. |
| Tmax of Encorafenib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of LHY746 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. |
| Tmax of Binimetinib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of AR00426032 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. |
| AUCinf of Encorafenib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| AUCinf of Binimetinib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| AUCinf of AR00426032 on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| T1/2 of Encorafenib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of LHY746 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib. |
| T1/2 of Binimetinib on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| AUC%Extrap of Encorafenib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. |
| T1/2 of AR00426032 on Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib. |
| AUC%Extrap of LHY746 on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. LHY746 was the metabolite of encorafenib. |
| AUC%Extrap of Binimetinib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. |
| AUC%Extrap of AR00426032 on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. AR00426032 was the metabolite of binimetinib. |
| Kel of Encorafenib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. |
| Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam. |
| Kel of Binimetinib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. |
| Kel of AR00426032 on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib. |
| CL/F of Encorafenib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). |
| CL/F of Binimetinib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). |
| Vz/F of Encorafenib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. |
| Vz/F of Binimetinib on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. |
| Cmax of Binimetinib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. |
| Cmax of AR00426032 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. |
| AUClast of Binimetinib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. |
| AUClast of AR00426032 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib. |
| Tmax of Encorafenib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of LHY746 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. |
| Tmax of Binimetinib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of AR00426032 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. |
| T1/2 of Encorafenib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of LHY746 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib. |
| T1/2 of Binimetinib on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. |
| T1/2 of AR00426032 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. |
| Number of Participants With Laboratory Abnormalities in the DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell \[RBC\],platelet,white blood cell count \[WBC\],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (\>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. |
| Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | Vital signs (temperature, pulse rate \[PR\]), systolic blood pressure \[SBP\]), and diastolic blood pressure \[DBP\]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP\>=100 millimeters of mercury (mm Hg)/less than or equal to (\<=) 50 mmHg with increase/decrease from baseline of \>=15 mmHg; SBP: \>=160 mmHg/\<=90 mmHg with increase/decrease from baseline of \>=20 mmHg; PR: \>=120 beats per minute (bpm)/\<=50 bpm with increase/decrease from baseline of \>=15 bpm; temperature for Arms 1 and 3: \>=37.5°C/\<=35°C; Arms 2: \>=37.5°C/\<=36°C. |
| Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF \>450 - \<=480 mesc, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. QT interval \>450 - \<=480 msec, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. Heart rate increase from baseline \>25% and value \>100 bpm and decrease from baseline \>25% and value \<60 bpm. PR interval increase from baseline \>25% and value \>200 msec. QRS interval increase from baseline \>25% and value \>110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure. |
| Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and \<-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE. |
| Kel of LHY746 on Day 1 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib. |
| Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine. |
| MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole. |
| MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion. |
| MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib. |
| MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole. |
| Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam. |
| MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine. |
| MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion. |
| MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib. |
| Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan. |
| MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 | 0 to 8 hours after dosing on Days -7, 1 and 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan. |
| Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. |
| Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine. |
| Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole. |
| Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. |
| Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion. |
| AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. |
| AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. |
| AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole. |
Countries
Belgium, Canada, Netherlands, Spain, United States
Participant flow
Pre-assignment details
This study was conducted in 3 Arms to evaluate the potential drug-drug interactions (DDIs) of single and multiple oral doses of encorafenib in combination with binimetinib with sensitive substrates of specific cytochrome P450 (CYP) enzymes (Arm 1), organic anion-transporting polypeptide (OATP)/breast cancer resistance protein (BCRP) transporters (Arm 2), and moderate CYP3A4 inducer (Arm 3). A total of 29, 12, 15 participants were enrolled in Arm 1, Arm 2, and Arm 3, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 - CYP Probe Cocktail Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | 27 |
| Arm 2 - Rosuvastatin and Bupropion Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | 12 |
| Arm 3 - Modafinil Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met.continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). | 15 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| DDI Phase | Adverse Event | 2 | 0 | 0 |
| DDI Phase | Physician Decision | 1 | 0 | 0 |
| DDI Phase | Progressive Disease | 1 | 0 | 0 |
| Post-DDI Phase | Adverse Event | 5 | 3 | 2 |
| Post-DDI Phase | Discretion of investigator | 1 | 1 | 0 |
| Post-DDI Phase | Progressive Disease | 11 | 6 | 13 |
| Post-DDI Phase | Study terminated by sponsor | 7 | 0 | 0 |
| Post-DDI Phase | Withdrawal of consent | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Arm 1 - CYP Probe Cocktail | Arm 2 - Rosuvastatin and Bupropion | Arm 3 - Modafinil | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 12.14 | 61.3 Years STANDARD_DEVIATION 13.65 | 58.9 Years STANDARD_DEVIATION 9.98 | 61.1 Years STANDARD_DEVIATION 11.9 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 11 Participants | 14 Participants | 50 Participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 13 Participants | 6 Participants | 8 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 12 | 0 / 15 | 1 / 25 | 2 / 12 | 3 / 15 |
| other Total, other adverse events | 25 / 27 | 9 / 12 | 11 / 15 | 4 / 25 | 4 / 12 | 3 / 15 |
| serious Total, serious adverse events | 2 / 27 | 1 / 12 | 0 / 15 | 11 / 25 | 3 / 12 | 4 / 15 |
Outcome results
Primary
Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 | Day -7 | 0.0264 mg | Geometric Coefficient of Variation 396.7 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 | Day 1 | 0.0323 mg | Geometric Coefficient of Variation 542.5 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 | Day 14 | 0.0225 mg | Geometric Coefficient of Variation 899.2 |
90% CI: [0.775, 1.87]
90% CI: [0.593, 1.49]
Primary
Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 | Day -7 | 3.78 mg | Geometric Coefficient of Variation 183.9 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 | Day 1 | 4.41 mg | Geometric Coefficient of Variation 165.5 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 | Day 14 | 3.55 mg | Geometric Coefficient of Variation 222.5 |
90% CI: [0.83, 1.67]
90% CI: [0.68, 1.41]
Primary
Ae0-8 of E-3174 on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 | Day -7 | 0.227 mg | Geometric Coefficient of Variation 293.3 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 | Day 1 | 0.332 mg | Geometric Coefficient of Variation 276.2 |
| Arm 1 - CYP Probe Cocktail | Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 | Day 14 | 0.205 mg | Geometric Coefficient of Variation 317.8 |
90% CI: [0.915, 2.36]
90% CI: [0.519, 1.39]
Primary
Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14
AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 25.7 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 57.2 |
| Arm 1 - CYP Probe Cocktail | Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 27.6 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 58.4 |
| Arm 1 - CYP Probe Cocktail | Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 4.52 nanograms*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 52.9 |
90% CI: [0.92, 1.25]
90% CI: [0.151, 0.204]
Primary
AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 | Day -7 | 313 ng*hr/mL | Geometric Coefficient of Variation 134.6 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 | Day 1 | 302 ng*hr/mL | Geometric Coefficient of Variation 92.1 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 | Day 14 | 195 ng*hr/mL | Geometric Coefficient of Variation 60.6 |
90% CI: [0.688, 1.39]
90% CI: [0.445, 0.9]
Primary
AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day -7 | 5940 ng*hr/mL | Geometric Coefficient of Variation 35.8 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day 1 | 6480 ng*hr/mL | Geometric Coefficient of Variation 34.4 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day 14 | 7520 ng*hr/mL | Geometric Coefficient of Variation 22.7 |
90% CI: [0.947, 1.26]
90% CI: [1.1, 1.46]
Primary
AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day -7 | 5100 ng*hr/mL | Geometric Coefficient of Variation 36.6 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day 1 | 5700 ng*hr/mL | Geometric Coefficient of Variation 45.7 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day 14 | 6430 ng*hr/mL | Geometric Coefficient of Variation 29.6 |
90% CI: [1.02, 1.23]
90% CI: [1.14, 1.38]
Primary
AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 339 ng*hr/mL | Geometric Coefficient of Variation 48.1 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 261 ng*hr/mL | Geometric Coefficient of Variation 49 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 250 ng*hr/mL | Geometric Coefficient of Variation 50.1 |
90% CI: [0.637, 0.928]
90% CI: [0.61, 0.889]
Primary
AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Day 14 | 11900 ng*hr/mL | Geometric Coefficient of Variation 35.8 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Day 21 | 9100 ng*hr/mL | Geometric Coefficient of Variation 30.3 |
90% CI: [0.613, 0.945]
Primary
AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 8.87 ng*hr/mL | Geometric Coefficient of Variation 43.7 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 11.1 ng*hr/mL | Geometric Coefficient of Variation 46.6 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 4.55 ng*hr/mL | Geometric Coefficient of Variation 62.6 |
90% CI: [1.09, 1.43]
90% CI: [0.449, 0.587]
Primary
AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day -7 | 125 ng*hr/mL | Geometric Coefficient of Variation 32 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day 1 | 160 ng*hr/mL | Geometric Coefficient of Variation 44.5 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day 14 | 133 ng*hr/mL | Geometric Coefficient of Variation 41 |
90% CI: [1.17, 1.39]
90% CI: [0.979, 1.16]
Primary
AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day -7 | 1090 ng*hr/mL | Geometric Coefficient of Variation 59.8 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 1 | 1080 ng*hr/mL | Geometric Coefficient of Variation 63.8 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 14 | 1610 ng*hr/mL | Geometric Coefficient of Variation 65.7 |
90% CI: [0.803, 1.23]
90% CI: [1.2, 1.83]
Primary
AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Day 14 | 31100 ng*hr/mL | Geometric Coefficient of Variation 45.4 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Day 21 | 33100 ng*hr/mL | Geometric Coefficient of Variation 31.2 |
90% CI: [0.929, 1.22]
Primary
AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day -7 | 815 ng*hr/mL | Geometric Coefficient of Variation 193.3 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day 1 | 1020 ng*hr/mL | Geometric Coefficient of Variation 91.9 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day 14 | 674 ng*hr/mL | Geometric Coefficient of Variation 54.3 |
90% CI: [0.8, 1.98]
90% CI: [0.526, 1.3]
Primary
AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day -7 | 2160 ng*hr/mL | Geometric Coefficient of Variation 47.7 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day 1 | 1940 ng*hr/mL | Geometric Coefficient of Variation 31.5 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day 14 | 1470 ng*hr/mL | Geometric Coefficient of Variation 64.6 |
90% CI: [0.721, 1.12]
90% CI: [0.544, 0.848]
Primary
AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day -7 | 33.6 ng*hr/mL | Geometric Coefficient of Variation 88.1 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 1 | 93.8 ng*hr/mL | Geometric Coefficient of Variation 97.9 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 14 | 52.8 ng*hr/mL | Geometric Coefficient of Variation 66.3 |
90% CI: [2.08, 3.74]
90% CI: [1.17, 2.11]
Primary
AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 135 ng*hr/mL | Geometric Coefficient of Variation 29.9 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 173 ng*hr/mL | Geometric Coefficient of Variation 41.8 |
| Arm 1 - CYP Probe Cocktail | AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 142 ng*hr/mL | Geometric Coefficient of Variation 38.9 |
90% CI: [1.18, 1.38]
90% CI: [0.974, 1.14]
Primary
Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 | Day -7 | 91.8 ng/mL | Geometric Coefficient of Variation 104.5 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 | Day 1 | 90.4 ng/mL | Geometric Coefficient of Variation 79.3 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 | Day 14 | 64.4 ng/mL | Geometric Coefficient of Variation 54.8 |
90% CI: [0.762, 1.33]
90% CI: [0.543, 0.948]
Primary
Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day -7 | 1150 ng/mL | Geometric Coefficient of Variation 31.5 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day 1 | 1210 ng/mL | Geometric Coefficient of Variation 30.6 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Day 14 | 1300 ng/mL | Geometric Coefficient of Variation 19.8 |
90% CI: [0.922, 1.2]
90% CI: [0.992, 1.29]
Primary
Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day -7 | 984 ng/mL | Geometric Coefficient of Variation 37.2 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day 1 | 1070 ng/mL | Geometric Coefficient of Variation 40.4 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Day 14 | 1110 ng/mL | Geometric Coefficient of Variation 29.7 |
90% CI: [0.99, 1.19]
90% CI: [1, 1.22]
Primary
Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 94.0 ng/mL | Geometric Coefficient of Variation 63.9 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 70.9 ng/mL | Geometric Coefficient of Variation 50.6 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 71.0 ng/mL | Geometric Coefficient of Variation 52.7 |
90% CI: [0.595, 0.954]
90% CI: [0.596, 0.957]
Primary
Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Day 14 | 3540 ng/mL | Geometric Coefficient of Variation 55.6 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Day 21 | 2830 ng/mL | Geometric Coefficient of Variation 67.2 |
90% CI: [0.585, 1.09]
Primary
Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 3.36 ng/mL | Geometric Coefficient of Variation 53.4 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 4.52 ng/mL | Geometric Coefficient of Variation 52.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 2.09 ng/mL | Geometric Coefficient of Variation 71.6 |
90% CI: [1.12, 1.62]
90% CI: [0.517, 0.748]
Primary
Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day -7 | 41.5 ng/mL | Geometric Coefficient of Variation 32.8 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day 1 | 45.4 ng/mL | Geometric Coefficient of Variation 43.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Day 14 | 54.1 ng/mL | Geometric Coefficient of Variation 29.1 |
90% CI: [0.975, 1.23]
90% CI: [1.16, 1.46]
Primary
Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day -7 | 181 ng/mL | Geometric Coefficient of Variation 46.9 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 1 | 189 ng/mL | Geometric Coefficient of Variation 49.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 14 | 256 ng/mL | Geometric Coefficient of Variation 62.5 |
90% CI: [0.864, 1.27]
90% CI: [1.17, 1.72]
Primary
Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Day 14 | 2460 ng/mL | Geometric Coefficient of Variation 24.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Day 21 | 2510 ng/mL | Geometric Coefficient of Variation 26.8 |
90% CI: [0.935, 1.11]
Primary
Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day -7 | 267 ng/mL | Geometric Coefficient of Variation 188.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day 1 | 354 ng/mL | Geometric Coefficient of Variation 73.1 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Day 14 | 271 ng/mL | Geometric Coefficient of Variation 57.1 |
90% CI: [0.861, 2.04]
90% CI: [0.659, 1.56]
Primary
Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day -7 | 357 ng/mL | Geometric Coefficient of Variation 41.6 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day 1 | 319 ng/mL | Geometric Coefficient of Variation 27.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Day 14 | 247 ng/mL | Geometric Coefficient of Variation 53.5 |
90% CI: [0.741, 1.08]
90% CI: [0.573, 0.835]
Primary
Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 1 | 30.3 ng/mL | Geometric Coefficient of Variation 130.8 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 14 | 18.7 ng/mL | Geometric Coefficient of Variation 113.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day -7 | 6.98 ng/mL | Geometric Coefficient of Variation 96.4 |
90% CI: [2.94, 6.4]
90% CI: [1.82, 3.96]
Primary
Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 45.2 ng/mL | Geometric Coefficient of Variation 31.5 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 50.5 ng/mL | Geometric Coefficient of Variation 40.8 |
| Arm 1 - CYP Probe Cocktail | Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 56.7 ng/mL | Geometric Coefficient of Variation 27.7 |
90% CI: [0.998, 1.25]
90% CI: [1.12, 1.4]
Primary
Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline pharmacokinetic (PK) sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day -7 | 9.45 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45.1 |
| Arm 1 - CYP Probe Cocktail | Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day 1 | 11.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 50.6 |
| Arm 1 - CYP Probe Cocktail | Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Day 14 | 2.44 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 54.6 |
90% CI: [0.978, 1.4]
90% CI: [0.215, 0.308]
Primary
The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 | Day -7 | 0.239 milligrams (mg) | Geometric Coefficient of Variation 268 |
| Arm 1 - CYP Probe Cocktail | The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 | Day 1 | 0.349 milligrams (mg) | Geometric Coefficient of Variation 314.2 |
| Arm 1 - CYP Probe Cocktail | The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 | Day 14 | 0.286 milligrams (mg) | Geometric Coefficient of Variation 277.3 |
90% CI: [0.902, 2.32]
90% CI: [0.72, 1.93]
Secondary
Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 73.9 Liters (L)/hour (h) | Geometric Coefficient of Variation 72.5 |
| Arm 1 - CYP Probe Cocktail | Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 73.9 Liters (L)/hour (h) | Geometric Coefficient of Variation 65.1 |
| Arm 1 - CYP Probe Cocktail | Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 392 Liters (L)/hour (h) | Geometric Coefficient of Variation 52.5 |
Secondary
Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 0.196 Fraction/hour | Geometric Coefficient of Variation 26.2 |
| Arm 1 - CYP Probe Cocktail | Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.188 Fraction/hour | Geometric Coefficient of Variation 22.6 |
| Arm 1 - CYP Probe Cocktail | Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.347 Fraction/hour | Geometric Coefficient of Variation 55.4 |
Secondary
Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 306 Litre | Geometric Coefficient of Variation 67.7 |
| Arm 1 - CYP Probe Cocktail | Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 339 Litre | Geometric Coefficient of Variation 54.6 |
| Arm 1 - CYP Probe Cocktail | Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 1030 Litre | Geometric Coefficient of Variation 54.7 |
Secondary
AUC%Extrap of AR00426032 on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of AR00426032 on Day 1 | 19.8 Percentage of AUC | Geometric Coefficient of Variation 33.8 |
Secondary
AUC%Extrap of Binimetinib on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Binimetinib on Day 1 | 13.7 Percentage of AUC | Geometric Coefficient of Variation 60.2 |
Secondary
AUC%Extrap of Encorafenib on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Encorafenib on Day 1 | 24.4 Percentage of AUC | Geometric Coefficient of Variation 73.9 |
Secondary
AUC%Extrap of LHY746 on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of LHY746 on Day 1 | 52.9 Percentage of AUC | Geometric Coefficient of Variation 56.1 |
Secondary
AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 26.1 Percentage of AUC | Geometric Coefficient of Variation 65.7 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 8.07 Percentage of AUC | Geometric Coefficient of Variation 66.7 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 12.4 Percentage of AUC | Geometric Coefficient of Variation 147.3 |
Secondary
AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 48.3 Percentage of AUC | Geometric Coefficient of Variation 39.4 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 53.2 Percentage of AUC | Geometric Coefficient of Variation 27 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 61.0 Percentage of AUC | Geometric Coefficient of Variation 26 |
Secondary
AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 46.7 Percentage of AUC | Geometric Coefficient of Variation 37.6 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 54.8 Percentage of AUC | Geometric Coefficient of Variation 25.5 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 58.0 Percentage of AUC | Geometric Coefficient of Variation 25.3 |
Secondary
AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 14.1 Percentage of AUC | Geometric Coefficient of Variation 42.6 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 12.9 Percentage of AUC | Geometric Coefficient of Variation 46.1 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 12.8 Percentage of AUC | Geometric Coefficient of Variation 68.1 |
Secondary
AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day -7 | 15.3 Percentage of AUC | Geometric Coefficient of Variation 35 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 1 | 22.6 Percentage of AUC | Geometric Coefficient of Variation 40.5 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 14 | 14.1 Percentage of AUC | Geometric Coefficient of Variation 54.9 |
Secondary
AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 7.35 Percentage of AUC | Geometric Coefficient of Variation 142.1 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 11.9 Percentage of AUC | Geometric Coefficient of Variation 141.2 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 4.22 Percentage of AUC | Geometric Coefficient of Variation 113.9 |
Secondary
AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 15.2 Percentage of AUC | Geometric Coefficient of Variation 35.2 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 21.9 Percentage of AUC | Geometric Coefficient of Variation 40.1 |
| Arm 1 - CYP Probe Cocktail | AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 12.6 Percentage of AUC | Geometric Coefficient of Variation 68.4 |
Secondary
AUCinf of AR00426032 on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number of analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of AR00426032 on Day 1 | 270 ng*hr/mL | Geometric Coefficient of Variation 40.5 |
| Arm 2 - Rosuvastatin and Bupropion | AUCinf of AR00426032 on Day 1 | 432 ng*hr/mL | Geometric Coefficient of Variation 32.4 |
Secondary
AUCinf of Binimetinib on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Binimetinib on Day 1 | 2970 ng*hr/mL | Geometric Coefficient of Variation 45.4 |
| Arm 2 - Rosuvastatin and Bupropion | AUCinf of Binimetinib on Day 1 | 3280 ng*hr/mL | Geometric Coefficient of Variation 47.7 |
Secondary
AUCinf of Encorafenib on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Encorafenib on Day 1 | 26200 ng*hr/mL | Geometric Coefficient of Variation 71.6 |
| Arm 2 - Rosuvastatin and Bupropion | AUCinf of Encorafenib on Day 1 | 45100 ng*hr/mL | Geometric Coefficient of Variation 56.8 |
Secondary
AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 557 ng*hr/mL | Geometric Coefficient of Variation 92.6 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 880 ng*hr/mL | Geometric Coefficient of Variation 21.8 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 294 ng*hr/mL | Geometric Coefficient of Variation 44.5 |
Secondary
AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 398 ng*hr/mL | Geometric Coefficient of Variation 54.9 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 390 ng*hr/mL | Geometric Coefficient of Variation 11.1 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 298 ng*hr/mL | Geometric Coefficient of Variation 38.4 |
Secondary
AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 9.98 ng*hr/mL | Geometric Coefficient of Variation 43.9 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 13.1 ng*hr/mL | Geometric Coefficient of Variation 44.9 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 5.52 ng*hr/mL | Geometric Coefficient of Variation 56.2 |
Secondary
AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day -7 | 139 ng*hr/mL | Geometric Coefficient of Variation 30.6 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 1 | 167 ng*hr/mL | Geometric Coefficient of Variation 52.4 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 14 | 143 ng*hr/mL | Geometric Coefficient of Variation 36.3 |
Secondary
AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 27.1 ng*hr/mL | Geometric Coefficient of Variation 72.5 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 27.1 ng*hr/mL | Geometric Coefficient of Variation 65.1 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 5.10 ng*hr/mL | Geometric Coefficient of Variation 52.5 |
Secondary
AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 1630 ng*hr/mL | Geometric Coefficient of Variation 151.6 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 1170 ng*hr/mL | Geometric Coefficient of Variation 79.4 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 904 ng*hr/mL | Geometric Coefficient of Variation 35.7 |
Secondary
AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day -7 | 75.4 ng*hr/mL | Geometric Coefficient of Variation 62.3 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 1 | 139 ng*hr/mL | Geometric Coefficient of Variation 69.8 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 14 | 62.9 ng*hr/mL | Geometric Coefficient of Variation 48.5 |
Secondary
AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 150 ng*hr/mL | Geometric Coefficient of Variation 27.7 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 172 ng*hr/mL | Geometric Coefficient of Variation 49.1 |
| Arm 1 - CYP Probe Cocktail | AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 154 ng*hr/mL | Geometric Coefficient of Variation 35.5 |
Secondary
AUClast of AR00426032 on Day 14 and Day 21
AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of AR00426032 on Day 14 and Day 21 | Day 14 | 114 ng*hr/mL | Geometric Coefficient of Variation 64.5 |
| Arm 1 - CYP Probe Cocktail | AUClast of AR00426032 on Day 14 and Day 21 | Day 21 | 112 ng*hr/mL | Geometric Coefficient of Variation 33 |
Secondary
AUClast of AR00426032 on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of AR00426032 on Day 1 and Day 14 | Day 1 | 236 ng*hr/mL | Geometric Coefficient of Variation 39.6 |
| Arm 1 - CYP Probe Cocktail | AUClast of AR00426032 on Day 1 and Day 14 | Day 14 | 108 ng*hr/mL | Geometric Coefficient of Variation 74.1 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of AR00426032 on Day 1 and Day 14 | Day 1 | 256 ng*hr/mL | Geometric Coefficient of Variation 74.8 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of AR00426032 on Day 1 and Day 14 | Day 14 | 122 ng*hr/mL | Geometric Coefficient of Variation 67.4 |
Secondary
AUClast of Binimetinib on Day 14 and Day 21
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Binimetinib on Day 14 and Day 21 | Day 14 | 2400 ng*hr/mL | Geometric Coefficient of Variation 38.6 |
| Arm 1 - CYP Probe Cocktail | AUClast of Binimetinib on Day 14 and Day 21 | Day 21 | 2290 ng*hr/mL | Geometric Coefficient of Variation 30.6 |
Secondary
AUClast of Binimetinib on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Binimetinib on Day 1 and Day 14 | Day 1 | 2290 ng*hr/mL | Geometric Coefficient of Variation 43.3 |
| Arm 1 - CYP Probe Cocktail | AUClast of Binimetinib on Day 1 and Day 14 | Day 14 | 2190 ng*hr/mL | Geometric Coefficient of Variation 33.8 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of Binimetinib on Day 1 and Day 14 | Day 1 | 2040 ng*hr/mL | Geometric Coefficient of Variation 81 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of Binimetinib on Day 1 and Day 14 | Day 14 | 2210 ng*hr/mL | Geometric Coefficient of Variation 40.7 |
Secondary
AUClast of Encorafenib on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of Encorafenib on Day 1 and Day 14 | Day 1 | 24500 ng*hr/mL | Geometric Coefficient of Variation 36.7 |
| Arm 1 - CYP Probe Cocktail | AUClast of Encorafenib on Day 1 and Day 14 | Day 14 | 12700 ng*hr/mL | Geometric Coefficient of Variation 37.6 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of Encorafenib on Day 1 and Day 14 | Day 1 | 25900 ng*hr/mL | Geometric Coefficient of Variation 61.7 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of Encorafenib on Day 1 and Day 14 | Day 14 | 13100 ng*hr/mL | Geometric Coefficient of Variation 28.6 |
Secondary
AUClast of LHY746 on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | AUClast of LHY746 on Day 1 and Day 14 | Day 1 | 5130 ng*hr/mL | Geometric Coefficient of Variation 66.1 |
| Arm 1 - CYP Probe Cocktail | AUClast of LHY746 on Day 1 and Day 14 | Day 14 | 34000 ng*hr/mL | Geometric Coefficient of Variation 34.4 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of LHY746 on Day 1 and Day 14 | Day 1 | 4990 ng*hr/mL | Geometric Coefficient of Variation 78.1 |
| Arm 2 - Rosuvastatin and Bupropion | AUClast of LHY746 on Day 1 and Day 14 | Day 14 | 32800 ng*hr/mL | Geometric Coefficient of Variation 54.5 |
Secondary
CL/F of Binimetinib on Day 1
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | CL/F of Binimetinib on Day 1 | 15.1 L/h | Geometric Coefficient of Variation 45.4 |
Secondary
CL/F of Encorafenib on Day 1
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | CL/F of Encorafenib on Day 1 | 17.2 L/h | Geometric Coefficient of Variation 71.6 |
Secondary
CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 12.3 L/h | Geometric Coefficient of Variation 151.6 |
| Arm 1 - CYP Probe Cocktail | CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 17.0 L/h | Geometric Coefficient of Variation 79.4 |
| Arm 1 - CYP Probe Cocktail | CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 22.1 L/h | Geometric Coefficient of Variation 35.7 |
Secondary
Cmax of AR00426032 on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of AR00426032 on Day 14 and Day 21 | Day 14 | 25.9 ng/mL | Geometric Coefficient of Variation 63.2 |
| Arm 1 - CYP Probe Cocktail | Cmax of AR00426032 on Day 14 and Day 21 | Day 21 | 24.7 ng/mL | Geometric Coefficient of Variation 36.7 |
Secondary
Cmax of AR00426032 on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of AR00426032 on Day 1 and Day 14 | Day 1 | 57.0 ng/mL | Geometric Coefficient of Variation 41.2 |
| Arm 1 - CYP Probe Cocktail | Cmax of AR00426032 on Day 1 and Day 14 | Day 14 | 23.3 ng/mL | Geometric Coefficient of Variation 85.6 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of AR00426032 on Day 1 and Day 14 | Day 1 | 63.3 ng/mL | Geometric Coefficient of Variation 73.2 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of AR00426032 on Day 1 and Day 14 | Day 14 | 27.4 ng/mL | Geometric Coefficient of Variation 43.1 |
Secondary
Cmax of Binimetinib on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Binimetinib on Day 14 and Day 21 | Day 14 | 660 ng/mL | Geometric Coefficient of Variation 39.7 |
| Arm 1 - CYP Probe Cocktail | Cmax of Binimetinib on Day 14 and Day 21 | Day 21 | 663 ng/mL | Geometric Coefficient of Variation 25.3 |
Secondary
Cmax of Binimetinib on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Binimetinib on Day 1 and Day 14 | Day 1 | 661 ng/mL | Geometric Coefficient of Variation 55.1 |
| Arm 1 - CYP Probe Cocktail | Cmax of Binimetinib on Day 1 and Day 14 | Day 14 | 521 ng/mL | Geometric Coefficient of Variation 59.9 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of Binimetinib on Day 1 and Day 14 | Day 1 | 549 ng/mL | Geometric Coefficient of Variation 89.5 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of Binimetinib on Day 1 and Day 14 | Day 14 | 566 ng/mL | Geometric Coefficient of Variation 63.1 |
Secondary
Cmax of Encorafenib on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of Encorafenib on Day 1 and Day 14 | Day 1 | 6150 ng/mL | Geometric Coefficient of Variation 41.9 |
| Arm 1 - CYP Probe Cocktail | Cmax of Encorafenib on Day 1 and Day 14 | Day 14 | 3240 ng/mL | Geometric Coefficient of Variation 55.7 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of Encorafenib on Day 1 and Day 14 | Day 1 | 6060 ng/mL | Geometric Coefficient of Variation 77.7 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of Encorafenib on Day 1 and Day 14 | Day 14 | 2940 ng/mL | Geometric Coefficient of Variation 72.2 |
Secondary
Cmax of LHY746 on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Cmax of LHY746 on Day 1 and Day 14 | Day 1 | 943 ng/mL | Geometric Coefficient of Variation 66.6 |
| Arm 1 - CYP Probe Cocktail | Cmax of LHY746 on Day 1 and Day 14 | Day 14 | 2490 ng/mL | Geometric Coefficient of Variation 32.4 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of LHY746 on Day 1 and Day 14 | Day 1 | 953 ng/mL | Geometric Coefficient of Variation 66 |
| Arm 2 - Rosuvastatin and Bupropion | Cmax of LHY746 on Day 1 and Day 14 | Day 14 | 2340 ng/mL | Geometric Coefficient of Variation 66.8 |
Secondary
Fe for Dextromethorphan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Fe for Dextromethorphan on Day -7, Day 1 and Day 14 | Day -7 | 0.0881 Percentage of dose | Geometric Coefficient of Variation 396.7 |
| Arm 1 - CYP Probe Cocktail | Fe for Dextromethorphan on Day -7, Day 1 and Day 14 | Day 1 | 0.108 Percentage of dose | Geometric Coefficient of Variation 542.5 |
| Arm 1 - CYP Probe Cocktail | Fe for Dextromethorphan on Day -7, Day 1 and Day 14 | Day 14 | 0.0750 Percentage of dose | Geometric Coefficient of Variation 899.2 |
Secondary
Fe for Dextrorphan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Fe for Dextrorphan on Day -7, Day 1 and Day 14 | Day -7 | 13.3 Percentage of dose | Geometric Coefficient of Variation 183.9 |
| Arm 1 - CYP Probe Cocktail | Fe for Dextrorphan on Day -7, Day 1 and Day 14 | Day 1 | 15.6 Percentage of dose | Geometric Coefficient of Variation 165.5 |
| Arm 1 - CYP Probe Cocktail | Fe for Dextrorphan on Day -7, Day 1 and Day 14 | Day 14 | 12.5 Percentage of dose | Geometric Coefficient of Variation 222.5 |
Secondary
Fe for E-3174 on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Fe for E-3174 on Day -7, Day 1 and Day 14 | Day -7 | 0.440 Percentage of dose | Geometric Coefficient of Variation 293.3 |
| Arm 1 - CYP Probe Cocktail | Fe for E-3174 on Day -7, Day 1 and Day 14 | Day 1 | 0.644 Percentage of dose | Geometric Coefficient of Variation 276.2 |
| Arm 1 - CYP Probe Cocktail | Fe for E-3174 on Day -7, Day 1 and Day 14 | Day 14 | 0.396 Percentage of dose | Geometric Coefficient of Variation 317.8 |
Secondary
Kel of AR00426032 on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of AR00426032 on Day 1 | 0.234 Fraction/hour | Geometric Coefficient of Variation 23.3 |
Secondary
Kel of Binimetinib on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Binimetinib on Day 1 | 0.265 Fraction/hour | Geometric Coefficient of Variation 35.4 |
Secondary
Kel of Encorafenib on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Encorafenib on Day 1 | 0.174 Fraction/hour | Geometric Coefficient of Variation 46.4 |
Secondary
Kel of LHY746 on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of LHY746 on Day 1 | 0.0732 Fraction/hour | Geometric Coefficient of Variation 130.1 |
Secondary
Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 0.303 Fraction/hour | Geometric Coefficient of Variation 43.1 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 0.197 Fraction/hour | Geometric Coefficient of Variation 45.7 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 0.386 Fraction/hour | Geometric Coefficient of Variation 22.5 |
Secondary
Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 0.0870 Fraction/hour | Geometric Coefficient of Variation 57.4 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.0753 Fraction/hour | Geometric Coefficient of Variation 61.3 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.0575 Fraction/hour | Geometric Coefficient of Variation 61.7 |
Secondary
Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 0.0893 Fraction/hour | Geometric Coefficient of Variation 70.3 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.0739 Fraction/hour | Geometric Coefficient of Variation 58.3 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.0656 Fraction/hour | Geometric Coefficient of Variation 54.4 |
Secondary
Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 0.231 Fraction/hour | Geometric Coefficient of Variation 24.2 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.236 Fraction/hour | Geometric Coefficient of Variation 31.1 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.269 Fraction/hour | Geometric Coefficient of Variation 47.2 |
Secondary
Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day -7 | 0.241 Fraction/hour | Geometric Coefficient of Variation 23.3 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.197 Fraction/hour | Geometric Coefficient of Variation 32.5 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.277 Fraction/hour | Geometric Coefficient of Variation 37.7 |
Secondary
Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 0.401 Fraction/hour | Geometric Coefficient of Variation 50.4 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 0.296 Fraction/hour | Geometric Coefficient of Variation 53.1 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 0.461 Fraction/hour | Geometric Coefficient of Variation 31.1 |
Secondary
Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 0.248 Fraction/hour | Geometric Coefficient of Variation 20.1 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.199 Fraction/hour | Geometric Coefficient of Variation 31.3 |
| Arm 1 - CYP Probe Cocktail | Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.259 Fraction/hour | Geometric Coefficient of Variation 36.9 |
Secondary
MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 | Day -7 | 151 Ratio | Geometric Coefficient of Variation 383.2 |
| Arm 1 - CYP Probe Cocktail | MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 | Day 1 | 144 Ratio | Geometric Coefficient of Variation 560.9 |
| Arm 1 - CYP Probe Cocktail | MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 | Day 14 | 167 Ratio | Geometric Coefficient of Variation 354.5 |
Secondary
MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 0.312 Ratio | Geometric Coefficient of Variation 49.8 |
| Arm 1 - CYP Probe Cocktail | MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 0.312 Ratio | Geometric Coefficient of Variation 119.8 |
| Arm 1 - CYP Probe Cocktail | MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 0.960 Ratio | Geometric Coefficient of Variation 92.6 |
Secondary
MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 0.309 Ratio | Geometric Coefficient of Variation 107.2 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 0.282 Ratio | Geometric Coefficient of Variation 87 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 0.277 Ratio | Geometric Coefficient of Variation 44.6 |
Secondary
MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 3.01 Ratio | Geometric Coefficient of Variation 60.2 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 3.88 Ratio | Geometric Coefficient of Variation 47.5 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 6.04 Ratio | Geometric Coefficient of Variation 57.5 |
Secondary
MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Day 14 | 3.31 Ratio | Geometric Coefficient of Variation 58.9 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Day 21 | 4.62 Ratio | Geometric Coefficient of Variation 43.3 |
Secondary
MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 0.392 Ratio | Geometric Coefficient of Variation 37.2 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.324 Ratio | Geometric Coefficient of Variation 44.5 |
| Arm 1 - CYP Probe Cocktail | MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.211 Ratio | Geometric Coefficient of Variation 72.3 |
Secondary
MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 0.273 Ratio | Geometric Coefficient of Variation 115.2 |
| Arm 1 - CYP Probe Cocktail | MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 0.244 Ratio | Geometric Coefficient of Variation 83 |
| Arm 1 - CYP Probe Cocktail | MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 0.227 Ratio | Geometric Coefficient of Variation 48.2 |
Secondary
MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 1.80 Ratio | Geometric Coefficient of Variation 61.1 |
| Arm 1 - CYP Probe Cocktail | MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 2.51 Ratio | Geometric Coefficient of Variation 50 |
| Arm 1 - CYP Probe Cocktail | MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 3.38 Ratio | Geometric Coefficient of Variation 48.8 |
Secondary
MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Day 14 | 0.883 Ratio | Geometric Coefficient of Variation 72.5 |
| Arm 1 - CYP Probe Cocktail | MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | Day 21 | 1.13 Ratio | Geometric Coefficient of Variation 77.6 |
Secondary
MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 0.335 Ratio | Geometric Coefficient of Variation 25.4 |
| Arm 1 - CYP Probe Cocktail | MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.285 Ratio | Geometric Coefficient of Variation 36.8 |
| Arm 1 - CYP Probe Cocktail | MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.205 Ratio | Geometric Coefficient of Variation 54.9 |
Secondary
Number of Participants With Laboratory Abnormalities in the DDI Phase
Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell \[RBC\],platelet,white blood cell count \[WBC\],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (\>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatinine CTCAE Graded High | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lipase CTCAE Graded High | 7 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded Low | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded Low | 3 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatine Kinase CTCAE Graded High | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Hemoglobin CTCAE Graded Low | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Neutrophils CTCAE Graded Low | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Amylase CTCAE Graded High | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded High | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded High | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatinine CTCAE Graded High | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Neutrophils CTCAE Graded Low | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lipase CTCAE Graded High | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded High | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded Low | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded Low | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded High | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Amylase CTCAE Graded High | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatine Kinase CTCAE Graded High | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Laboratory Abnormalities in the DDI Phase | Hemoglobin CTCAE Graded Low | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatine Kinase CTCAE Graded High | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Hemoglobin CTCAE Graded Low | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded Low | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lymphocytes CTCAE Graded High | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Neutrophils CTCAE Graded Low | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Amylase CTCAE Graded High | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Creatinine CTCAE Graded High | 3 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded High | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Lipase CTCAE Graded High | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Laboratory Abnormalities in the DDI Phase | Glucose CTCAE Graded Low | 1 Count of Participants |
Secondary
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase
LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and \<-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase | 4 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase | 0 Count of Participants |
Secondary
Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase
Vital signs (temperature, pulse rate \[PR\]), systolic blood pressure \[SBP\]), and diastolic blood pressure \[DBP\]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP\>=100 millimeters of mercury (mm Hg)/less than or equal to (\<=) 50 mmHg with increase/decrease from baseline of \>=15 mmHg; SBP: \>=160 mmHg/\<=90 mmHg with increase/decrease from baseline of \>=20 mmHg; PR: \>=120 beats per minute (bpm)/\<=50 bpm with increase/decrease from baseline of \>=15 bpm; temperature for Arms 1 and 3: \>=37.5°C/\<=35°C; Arms 2: \>=37.5°C/\<=36°C.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP high (>=160mmHg with increase from baseline of >=20mmHg) | 4 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP low (<=90mmHg with decrease from baseline of >=20mmHg) | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP high (>=100mmHg with increase from baseline of >=15mmHg) | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP low (<=50mmHg with decrease from baseline of >=15mmHg) | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR high (>=120bpm with increase from baseline of >=15bpm) | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR low (<=50bpm with decrease from baseline of >=15bpm） | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature high | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature low | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP high (>=100mmHg with increase from baseline of >=15mmHg) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature high | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP low (<=50mmHg with decrease from baseline of >=15mmHg) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR high (>=120bpm with increase from baseline of >=15bpm) | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR low (<=50bpm with decrease from baseline of >=15bpm） | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP high (>=160mmHg with increase from baseline of >=20mmHg) | 4 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP low (<=90mmHg with decrease from baseline of >=20mmHg) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature low | 3 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP high (>=100mmHg with increase from baseline of >=15mmHg) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP low (<=90mmHg with decrease from baseline of >=20mmHg) | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | SBP high (>=160mmHg with increase from baseline of >=20mmHg) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | DBP low (<=50mmHg with decrease from baseline of >=15mmHg) | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature high | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR low (<=50bpm with decrease from baseline of >=15bpm） | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | PR high (>=120bpm with increase from baseline of >=15bpm) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Temperature low | 1 Count of Participants |
Secondary
Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase
Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF \>450 - \<=480 mesc, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. QT interval \>450 - \<=480 msec, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. Heart rate increase from baseline \>25% and value \>100 bpm and decrease from baseline \>25% and value \<60 bpm. PR interval increase from baseline \>25% and value \>200 msec. QRS interval increase from baseline \>25% and value \>110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib. Here, 'Number Analyzed' signifies participants evaluable for the specified rows.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Increase from baseline >25% and value >100 bpm | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >450 - <=480 msec | 6 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >500 msec | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >60 msec | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >480 - <=500 msec | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >480 - <=500 msec | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >30 - <=60 msec | 13 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >500 msec | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Decrease from baseline >25% and value <60 bpm | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >30 - <=60 msec | 5 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QRS Increase from baseline >25% and value >110 msec | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >450 - <=480 mesc | 6 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >60 msec | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New PR Increase from baseline >25% and value >200 msec | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Increase from baseline >25% and value >100 bpm | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >450 - <=480 mesc | 3 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >480 - <=500 msec | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >500 msec | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >30 - <=60 msec | 3 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >60 msec | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >450 - <=480 msec | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >480 - <=500 msec | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >500 msec | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >30 - <=60 msec | 5 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >60 msec | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Decrease from baseline >25% and value <60 bpm | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New PR Increase from baseline >25% and value >200 msec | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QRS Increase from baseline >25% and value >110 msec | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New PR Increase from baseline >25% and value >200 msec | 3 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >60 msec | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >60 msec | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF Increase from baseline >30 - <=60 msec | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Increase from baseline >25% and value >100 bpm | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >500 msec | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >450 - <=480 mesc | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New Heart rate Decrease from baseline >25% and value <60 bpm | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QTcF >480 - <=500 msec | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >500 msec | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >480 - <=500 msec | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QRS Increase from baseline >25% and value >110 msec | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT Increase from baseline >30 - <=60 msec | 9 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | New QT >450 - <=480 msec | 4 Count of Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase
An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (all-causality) | 3 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality TEAEs | 26 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (all-causality) | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (treatment-related) | 8 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (treatment-related) | 8 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (all-causality) | 10 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality SAEs | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Deaths | 0 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (all-causality) | 13 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related SAEs | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related TEAEs | 24 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (all-causality) | 4 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality TEAEs | 9 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related TEAEs | 6 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality SAEs | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related SAEs | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (all-causality) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (all-causality) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (all-causality) | 8 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (treatment-related) | 6 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Deaths | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (all-causality) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related SAEs | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (treatment-related) | 8 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose reduction (treatment-related) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality SAEs | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with all-causality TEAEs | 11 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring additional therapy (all-causality) | 10 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (all-causality) | 4 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Participants with treatment-related TEAEs | 10 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs requiring dose interruption (treatment-related) | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | AEs leading to study drug discontinuation (all-causality) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | Deaths | 0 Count of Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase
Population: All participants who received at least 1 dose of encorafenib/binimetinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (treatment-related) | 7 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (all-causality) | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 2 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality SAEs | 11 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (treatment-related) | 7 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (all-causality) | 10 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality TEAEs | 17 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related TEAEs | 10 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (all-causality) | 14 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related SAEs | 4 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Deaths | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (treatment-related) | 1 Count of Participants |
| Arm 1 - CYP Probe Cocktail | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (all-causality) | 4 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (all-causality) | 3 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality TEAEs | 5 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related TEAEs | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality SAEs | 3 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related SAEs | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (all-causality) | 1 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (all-causality) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (treatment-related) | 0 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (all-causality) | 4 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (treatment-related) | 2 Count of Participants |
| Arm 2 - Rosuvastatin and Bupropion | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Deaths | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (all-causality) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related SAEs | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (treatment-related) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose reduction (treatment-related) | 0 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality SAEs | 4 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with all-causality TEAEs | 4 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring additional therapy (all-causality) | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (all-causality) | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (treatment-related) | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Participants with treatment-related TEAEs | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs requiring dose interruption (treatment-related) | 1 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | AEs leading to study drug discontinuation (all-causality) | 2 Count of Participants |
| Arm 3 - Modafinil (DDI Phase) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | Deaths | 3 Count of Participants |
Secondary
Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.
Time frame: Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 | Day -7 | 0.478 Percentage of dose | Geometric Coefficient of Variation 268 |
| Arm 1 - CYP Probe Cocktail | Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 | Day 1 | 0.699 Percentage of dose | Geometric Coefficient of Variation 314.2 |
| Arm 1 - CYP Probe Cocktail | Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 | Day 14 | 0.572 Percentage of dose | Geometric Coefficient of Variation 277.3 |
Secondary
Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 19.1 percentage of AUC | Geometric Coefficient of Variation 46 |
| Arm 1 - CYP Probe Cocktail | Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 19.3 percentage of AUC | Geometric Coefficient of Variation 37.6 |
| Arm 1 - CYP Probe Cocktail | Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 8.76 percentage of AUC | Geometric Coefficient of Variation 55.2 |
Secondary
Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14 | Day -7 | 0.920 Ratio | Geometric Coefficient of Variation 65.6 |
| Arm 1 - CYP Probe Cocktail | Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14 | Day 1 | 0.921 Ratio | Geometric Coefficient of Variation 100 |
| Arm 1 - CYP Probe Cocktail | Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14 | Day 14 | 0.693 Ratio | Geometric Coefficient of Variation 99 |
Secondary
Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 4.31 Ratio | Geometric Coefficient of Variation 68.6 |
| Arm 1 - CYP Probe Cocktail | Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 5.21 Ratio | Geometric Coefficient of Variation 87.8 |
| Arm 1 - CYP Probe Cocktail | Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 29.5 Ratio | Geometric Coefficient of Variation 70.3 |
Secondary
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 5.00 Ratio | Geometric Coefficient of Variation 63.3 |
| Arm 1 - CYP Probe Cocktail | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 5.97 Ratio | Geometric Coefficient of Variation 72.6 |
| Arm 1 - CYP Probe Cocktail | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 30.1 Ratio | Geometric Coefficient of Variation 65.7 |
Secondary
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 4.56 Ratio | Geometric Coefficient of Variation 54.7 |
| Arm 1 - CYP Probe Cocktail | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 4.36 Ratio | Geometric Coefficient of Variation 62.8 |
| Arm 1 - CYP Probe Cocktail | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 22.2 Ratio | Geometric Coefficient of Variation 60.6 |
Secondary
T1/2 of AR00426032 on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of AR00426032 on Day 14 and Day 21 | Day 14 | 5.60 Hours | Geometric Coefficient of Variation 37.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of AR00426032 on Day 14 and Day 21 | Day 21 | 5.22 Hours | Geometric Coefficient of Variation 58.7 |
Secondary
T1/2 of AR00426032 on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of AR00426032 on Day 1 and Day 14 | Day 1 | 2.96 Hours | Geometric Coefficient of Variation 23.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of AR00426032 on Day 1 and Day 14 | Day 14 | 3.97 Hours | Geometric Coefficient of Variation 42.6 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of AR00426032 on Day 1 and Day 14 | Day 1 | 3.15 Hours | Geometric Coefficient of Variation 24.7 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of AR00426032 on Day 1 and Day 14 | Day 14 | 3.89 Hours | Geometric Coefficient of Variation 51.9 |
Secondary
T1/2 of Binimetinib on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Binimetinib on Day 14 and Day 21 | Day 14 | 4.62 Hours | Geometric Coefficient of Variation 42.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Binimetinib on Day 14 and Day 21 | Day 21 | 4.55 Hours | Geometric Coefficient of Variation 44.8 |
Secondary
T1/2 of Binimetinib on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Binimetinib on Day 1 and Day 14 | Day 1 | 2.62 Hours | Geometric Coefficient of Variation 35.4 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Binimetinib on Day 1 and Day 14 | Day 14 | 3.90 Hours | Geometric Coefficient of Variation 39.9 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of Binimetinib on Day 1 and Day 14 | Day 1 | 2.45 Hours | Geometric Coefficient of Variation 17.3 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of Binimetinib on Day 1 and Day 14 | Day 14 | 3.70 Hours | Geometric Coefficient of Variation 42.8 |
Secondary
T1/2 of Encorafenib on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Encorafenib on Day 14 and Day 21 | Day 14 | 3.48 Hours | Geometric Coefficient of Variation 26.6 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Encorafenib on Day 14 and Day 21 | Day 21 | 3.57 Hours | Geometric Coefficient of Variation 27.3 |
Secondary
T1/2 of Encorafenib on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Encorafenib on Day 1 and Day 14 | Day 14 | 4.37 Hours | Geometric Coefficient of Variation 42.7 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Encorafenib on Day 1 and Day 14 | Day 1 | 3.98 Hours | Geometric Coefficient of Variation 46.4 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of Encorafenib on Day 1 and Day 14 | Day 1 | 3.77 Hours | Geometric Coefficient of Variation 37 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of Encorafenib on Day 1 and Day 14 | Day 14 | 3.58 Hours | Geometric Coefficient of Variation 13.7 |
Secondary
T1/2 of LHY746 on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of LHY746 on Day 14 and Day 21 | Day 14 | 8.67 Hours | Geometric Coefficient of Variation 33.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of LHY746 on Day 14 and Day 21 | Day 21 | 8.01 Hours | Geometric Coefficient of Variation 18.8 |
Secondary
T1/2 of LHY746 on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of LHY746 on Day 1 and Day 14 | Day 1 | 9.47 Hours | Geometric Coefficient of Variation 130.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of LHY746 on Day 1 and Day 14 | Day 14 | 9.27 Hours | Geometric Coefficient of Variation 40 |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of LHY746 on Day 1 and Day 14 | Day 1 | 22.5 Hours | — |
| Arm 2 - Rosuvastatin and Bupropion | T1/2 of LHY746 on Day 1 and Day 14 | Day 14 | 11.2 Hours | Geometric Coefficient of Variation 20.6 |
Secondary
T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 2.29 Hours | Geometric Coefficient of Variation 43.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 3.53 Hours | Geometric Coefficient of Variation 45.7 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 1.80 Hours | Geometric Coefficient of Variation 22.5 |
Secondary
T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 7.97 Hours | Geometric Coefficient of Variation 57.4 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 9.20 Hours | Geometric Coefficient of Variation 61.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 12.1 Hours | Geometric Coefficient of Variation 61.7 |
Secondary
T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 7.76 Hours | Geometric Coefficient of Variation 70.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 9.38 Hours | Geometric Coefficient of Variation 58.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 10.6 Hours | Geometric Coefficient of Variation 54.4 |
Secondary
T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 2.81 Hours | Geometric Coefficient of Variation 15.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 3.24 Hours | Geometric Coefficient of Variation 10.2 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 2.75 Hours | Geometric Coefficient of Variation 15.2 |
Secondary
T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 3.00 Hours | Geometric Coefficient of Variation 24.2 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 2.93 Hours | Geometric Coefficient of Variation 31.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 2.58 Hours | Geometric Coefficient of Variation 47.2 |
Secondary
T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day -7 | 2.87 Hours | Geometric Coefficient of Variation 23.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 1 | 3.53 Hours | Geometric Coefficient of Variation 32.5 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 14 | 2.50 Hours | Geometric Coefficient of Variation 37.7 |
Secondary
T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 1.73 Hours | Geometric Coefficient of Variation 50.4 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 2.34 Hours | Geometric Coefficient of Variation 53.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 1.50 Hours | Geometric Coefficient of Variation 31.1 |
Secondary
T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day -7 | 3.25 Hours | Geometric Coefficient of Variation 51.8 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 1 | 2.13 Hours | Geometric Coefficient of Variation 17 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 14 | 1.86 Hours | Geometric Coefficient of Variation 23 |
Secondary
T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 2.80 Hours | Geometric Coefficient of Variation 20.1 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 3.48 Hours | Geometric Coefficient of Variation 31.3 |
| Arm 1 - CYP Probe Cocktail | T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 2.68 Hours | Geometric Coefficient of Variation 36.9 |
Secondary
Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 3.54 Hours | Geometric Coefficient of Variation 26.2 |
| Arm 1 - CYP Probe Cocktail | Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 2.00 Hours | Geometric Coefficient of Variation 55.4 |
| Arm 1 - CYP Probe Cocktail | Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 3.69 Hours | Geometric Coefficient of Variation 22.6 |
Secondary
Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.88 Hours |
| Arm 1 - CYP Probe Cocktail | Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.88 Hours |
Secondary
Tmax of AR00426032 on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of AR00426032 on Day 14 and Day 21 | Day 14 | 2.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of AR00426032 on Day 14 and Day 21 | Day 21 | 2.00 Hours |
Secondary
Tmax of AR00426032 on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of AR00426032 on Day 1 and Day 14 | Day 1 | 2.02 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of AR00426032 on Day 1 and Day 14 | Day 14 | 2.00 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of AR00426032 on Day 1 and Day 14 | Day 1 | 2.48 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of AR00426032 on Day 1 and Day 14 | Day 14 | 2.00 Hours |
Secondary
Tmax of Binimetinib on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Binimetinib on Day 14 and Day 21 | Day 14 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Binimetinib on Day 14 and Day 21 | Day 21 | 1.00 Hours |
Secondary
Tmax of Binimetinib on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Binimetinib on Day 1 and Day 14 | Day 1 | 1.97 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Binimetinib on Day 1 and Day 14 | Day 14 | 1.98 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of Binimetinib on Day 1 and Day 14 | Day 1 | 1.97 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of Binimetinib on Day 1 and Day 14 | Day 14 | 1.93 Hours |
Secondary
Tmax of Encorafenib on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Encorafenib on Day 14 and Day 21 | Day 14 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Encorafenib on Day 14 and Day 21 | Day 21 | 1.00 Hours |
Secondary
Tmax of Encorafenib on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Encorafenib on Day 1 and Day 14 | Day 14 | 1.94 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Encorafenib on Day 1 and Day 14 | Day 1 | 2.00 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of Encorafenib on Day 1 and Day 14 | Day 1 | 1.87 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of Encorafenib on Day 1 and Day 14 | Day 14 | 1.93 Hours |
Secondary
Tmax of LHY746 on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Population: All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of LHY746 on Day 14 and Day 21 | Day 14 | 2.05 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of LHY746 on Day 14 and Day 21 | Day 21 | 2.10 Hours |
Secondary
Tmax of LHY746 on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Population: All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of LHY746 on Day 1 and Day 14 | Day 1 | 6.93 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of LHY746 on Day 1 and Day 14 | Day 14 | 2.98 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of LHY746 on Day 1 and Day 14 | Day 1 | 7.42 Hours |
| Arm 2 - Rosuvastatin and Bupropion | Tmax of LHY746 on Day 1 and Day 14 | Day 14 | 3.47 Hours |
Secondary
Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 2.97 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 3.80 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 3.00 Hours |
Secondary
Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.93 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.90 Hours |
Secondary
Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 1 | 0.94 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Day 14 | 0.98 Hours |
Secondary
Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day -7 | 1.87 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 1 | 1.93 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Day 14 | 1.92 Hours |
Secondary
Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.90 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.92 Hours |
Secondary
Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.90 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.88 Hours |
Secondary
Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day -7 | 4.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 1 | 7.68 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Day 14 | 3.94 Hours |
Secondary
Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 2.20 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 3.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 3.00 Hours |
Secondary
Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 | Day -7 | 7.18 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 | Day 1 | 7.63 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 | Day 14 | 6.00 Hours |
Secondary
Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day -7 | 2.40 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 1 | 1.85 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Day 14 | 1.40 Hours |
Secondary
Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day -7 | 1.00 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 1 | 0.90 Hours |
| Arm 1 - CYP Probe Cocktail | Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Day 14 | 0.88 Hours |
Secondary
Vz/F of Binimetinib on Day 1
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Vz/F of Binimetinib on Day 1 | 47.6 Litre | Geometric Coefficient of Variation 50.5 |
Secondary
Vz/F of Encorafenib on Day 1
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number of analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Vz/F of Encorafenib on Day 1 | 53.4 Litre | Geometric Coefficient of Variation 38.2 |
Secondary
Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Population: All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1 - CYP Probe Cocktail | Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day -7 | 29.1 Litre | Geometric Coefficient of Variation 93.9 |
| Arm 1 - CYP Probe Cocktail | Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 1 | 44.6 Litre | Geometric Coefficient of Variation 63.7 |
| Arm 1 - CYP Probe Cocktail | Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Day 14 | 45.9 Litre | Geometric Coefficient of Variation 39.3 |