Healthy
Conditions
Keywords
Encorafenib, Rabeprazole, Healthy adult participants
Brief summary
Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations
Detailed description
In order to decrease the size of the current formulated encorafenib capsule and improve the physical stability, 2 new encorafenib tablet formulations have been developed. This study is intended to select the optimal tablet formulation for commercialization based on the tablet pharmacokinetics. A preliminary assessment of the effect of a proton-pump inhibitor on the pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in the formulation selection.
Interventions
DRUGEncorafenib capsule formulation (CAP)
A single encorafenib dose of the CAP formulation
DRUGEncorafenib first formulation
first formulation
DRUGEncorafenib second formulation
second formulation
DRUGRabeprazole tablet
Proton-pump inhibitor
Sponsors
Ono Pharmaceutical Co. Ltd
Pierre Fabre Laboratories
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participants must be male or female of non-childbearing potential of 18 years of age or older, inclusive, at the time of signing the informed consent document. * Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. * Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight \>50 kg (110 lb). * Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and the protocol.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. Evidence of any active and uncontrolled bacterial or viral infection. * Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). * History of human immunodeficiency virus infection, hepatitis B, or hepatitis C; positive testing for human immunodeficiency virus, Hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C virus antibody. Hepatitis B vaccination is allowed. * Positive COVID-19 test at first admission. * Other medical or psychiatric conditions, laboratory test abnormalities, other conditions or situations related to COVID-19 pandemic or, in the investigator's judgment, make the participant inappropriate for the study. * Use of prescription or non-prescription medications within 7 days prior to the first dose of encorafenib with the exception of moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose. * History of known sensitivity to rabeprazole, substituted benzimidazoles or to any component of the rabeprazole formulation. * Previous administration with an investigational product (drug or vaccine) within 30 days. * Known hypersensitivity to encorafenib or its excipients. * A positive urine drug or cotinine test. * Screening supine blood pressure ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. * Baseline standard 12 lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. * Aspartate transaminase or alanine aminotransferase level ≥ 1.5 × upper limit of normal. * Total bilirubin level ≥1.5 × upper limit of normal. * Estimated glomerular filtration rate \<60 ml/min/1.73 m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | AUCinf for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by AUClast + (Clast/kel), where AUClast was the area under the plasma concentration-time profile from time zero to last quantifiable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was first-order elimination rate constant. |
| Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | Cmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data. |
| Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | AUClast for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated using Linear/Log trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | Vz/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/(AUCinf \* kel) after oral dose. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline) | 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. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occurred during follow-up within the lag time of up to 28 days after the last encorafenib dose were counted as treatment emergent and attributed to the last treatment taken. Events that occurred during the washout period (up to 28 days from the last treatment) between study periods were counted as treatment emergent and attributed to the previous treatment taken. |
| Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | Tmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data as time of first occurrence. |
| Number of Participants Meeting Vital Signs Categorical Criteria | Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline) | Supine blood pressure (BP) and pulse rate (PR) were measured at times specified. For Periods 1 to 3, the baseline measurement was the predose measurement on Day -1 of each period. For Period 4, the baseline measurement was the predose measurement on Day -1 of Period 3. The reported categories included: systolic blood pressure (SBP)\>=90mmHg; change from baseline (CFB) in SBP\>=30mmHg; diastolic blood pressure (DBP)\<50mmHg; CFB in DBP\>=20mmHg; PR\<40 beats per minute (bpm) or PR\>120bpm. Only those categories in which at least 1 participant had data were provided. |
| Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline) | Absolute values and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by protocol pre-defined categorization criterion. QTcF were derived using Fridericia's heart rate correction formula. For each period, triplicate ECGs were conducted predose on Day 1; all other ECG measurements were single ECGs. The baseline ECG value was the average of the triplicate ECG measurements collected before dose administration on Day 1. Changes from baseline were defined as the change between the postdose ECG measurement and the derived baseline ECG. |
| Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline) | Haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards. The assessment did not take into account whether each participants's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. The baseline measurement for safety laboratory tests for all periods was the predose measurement on Day -1 of Period 1. Only those categories in which at least 1 participant had data were reported. |
| Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | t½ for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. |
| Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose | CL/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/AUCinf after oral dose. |
Countries
United States
Participant flow
Pre-assignment details
A total of 18 participants were enrolled and randomized into 1 of the 6 treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants enrolled in this study | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 2 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous Mean (SD) | 46.5 Years STANDARD_DEVIATION 15.93 |
| Age, Customized 18-44 Years | 9 Participants |
| Age, Customized 45-64 Years | 7 Participants |
| Age, Customized >=65 Years | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants |
| Race/Ethnicity, Customized Black or African American, White | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 13 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 13 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 17 | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 11 / 18 | 11 / 18 | 8 / 17 | 1 / 8 | 5 / 9 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 17 | 0 / 8 | 0 / 9 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
AUCinf for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by AUClast + (Clast/kel), where AUClast was the area under the plasma concentration-time profile from time zero to last quantifiable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was first-order elimination rate constant.
Time frame: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2895 ng*hr/mL | Geometric Coefficient of Variation 44 |
| 75mg Encorafenib eMCCL, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2909 ng*hr/mL | Geometric Coefficient of Variation 49 |
| 75mg Encorafenib CAP, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2957 ng*hr/mL | Geometric Coefficient of Variation 41 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2825 ng*hr/mL | Geometric Coefficient of Variation 35 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2556 ng*hr/mL | Geometric Coefficient of Variation 63 |
Comparison: Natural log transformed encorafenib AUCinf was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [90.82, 99.9]
Comparison: Natural log transformed encorafenib AUCinf was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [91.71, 101.12]
Comparison: Natural log transformed encorafenib AUCinf was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to eMCC with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to eMCC with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [82.91, 112.47]
Comparison: Natural log transformed encorafenib AUCinf was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to eMCCL with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to eMCCL with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [82.59, 94.95]
Primary
Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
AUClast for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated using Linear/Log trapezoidal method.
Time frame: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2879 ng*hr/mL | Geometric Coefficient of Variation 44 |
| 75mg Encorafenib eMCCL, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2858 ng*hr/mL | Geometric Coefficient of Variation 48 |
| 75mg Encorafenib CAP, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2934 ng*hr/mL | Geometric Coefficient of Variation 41 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2635 ng*hr/mL | Geometric Coefficient of Variation 37 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 2529 ng*hr/mL | Geometric Coefficient of Variation 65 |
Comparison: Natural log transformed encorafenib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [90.37, 100.59]
Comparison: Natural log transformed encorafenib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [89.73, 99.88]
Comparison: Natural log transformed encorafenib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to eMCC with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to eMCC with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [84.1, 109.04]
Comparison: Natural log transformed encorafenib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to eMCCL with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to eMCCL with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [82.36, 94.7]
Primary
Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
Cmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data.
Time frame: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 898.4 ng/mL | Geometric Coefficient of Variation 46 |
| 75mg Encorafenib eMCCL, Fasted | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 778.2 ng/mL | Geometric Coefficient of Variation 45 |
| 75mg Encorafenib CAP, Fasted | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 845.8 ng/mL | Geometric Coefficient of Variation 36 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 686.0 ng/mL | Geometric Coefficient of Variation 43 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 631.7 ng/mL | Geometric Coefficient of Variation 70 |
Comparison: Natural log transformed encorafenib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [91.4, 119.04]
Comparison: Natural log transformed encorafenib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to CAP) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to CAP) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [79.17, 103.12]
Comparison: Natural log transformed encorafenib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCC relative to eMCC with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCC relative to eMCC with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [58.7, 108.08]
Comparison: Natural log transformed encorafenib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and participant within sequence as a random effect. The adjusted mean differences (eMCCL relative to eMCCL with rabeprazole) and corresponding 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (eMCCL relative to eMCCL with rabeprazole) and 90% CIs for the ratios. The geometric mean ratios are presented as percentages.90% CI: [64.82, 100.68]
Secondary
Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
CL/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/AUCinf after oral dose.
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 25.91 L/hr | Geometric Coefficient of Variation 44 |
| 75mg Encorafenib eMCCL, Fasted | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 25.81 L/hr | Geometric Coefficient of Variation 49 |
| 75mg Encorafenib CAP, Fasted | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 25.38 L/hr | Geometric Coefficient of Variation 41 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 26.53 L/hr | Geometric Coefficient of Variation 34 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 29.34 L/hr | Geometric Coefficient of Variation 64 |
Secondary
Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
Vz/F for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Dose/(AUCinf \* kel) after oral dose.
Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 166.1 Liters | Geometric Coefficient of Variation 46 |
| 75mg Encorafenib eMCCL, Fasted | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 165.1 Liters | Geometric Coefficient of Variation 49 |
| 75mg Encorafenib CAP, Fasted | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 161.7 Liters | Geometric Coefficient of Variation 46 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 159.3 Liters | Geometric Coefficient of Variation 29 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 209 Liters | Geometric Coefficient of Variation 56 |
Secondary
Number of Participants Meeting Vital Signs Categorical Criteria
Supine blood pressure (BP) and pulse rate (PR) were measured at times specified. For Periods 1 to 3, the baseline measurement was the predose measurement on Day -1 of each period. For Period 4, the baseline measurement was the predose measurement on Day -1 of Period 3. The reported categories included: systolic blood pressure (SBP)\>=90mmHg; change from baseline (CFB) in SBP\>=30mmHg; diastolic blood pressure (DBP)\<50mmHg; CFB in DBP\>=20mmHg; PR\<40 beats per minute (bpm) or PR\>120bpm. Only those categories in which at least 1 participant had data were provided.
Time frame: Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline)
Population: All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Number of Participants Meeting Vital Signs Categorical Criteria | 1 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants Meeting Vital Signs Categorical Criteria | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants Meeting Vital Signs Categorical Criteria | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants Meeting Vital Signs Categorical Criteria | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants Meeting Vital Signs Categorical Criteria | 0 Participants |
Secondary
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality
Haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards. The assessment did not take into account whether each participants's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. The baseline measurement for safety laboratory tests for all periods was the predose measurement on Day -1 of Period 1. Only those categories in which at least 1 participant had data were reported.
Time frame: Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline)
Population: All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received. Specifically, number of participants analyzed in the table is the total number of participants with at least one observation of the given laboratory test while on study treatment or during lag time.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | HEMATOLOGY - Monocytes/Leukocytes (%) > 1.2 x Upper Limit of Normal (ULN) | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | URINALYSIS - Urobilinogen (EU) >= 1 | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | HEMATOLOGY - Monocytes/Leukocytes (%) > 1.2 x Upper Limit of Normal (ULN) | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | URINALYSIS - Urobilinogen (EU) >= 1 | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | HEMATOLOGY - Monocytes/Leukocytes (%) > 1.2 x Upper Limit of Normal (ULN) | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | URINALYSIS - Urobilinogen (EU) >= 1 | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | HEMATOLOGY - Monocytes/Leukocytes (%) > 1.2 x Upper Limit of Normal (ULN) | 3 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | URINALYSIS - Urobilinogen (EU) >= 1 | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN | 1 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | CLINICAL CHEMISTRY - Urate (mg/dL) > 1.2x ULN | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | HEMATOLOGY - Monocytes/Leukocytes (%) > 1.2 x Upper Limit of Normal (ULN) | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | URINALYSIS - Urobilinogen (EU) >= 1 | 1 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
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. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occurred during follow-up within the lag time of up to 28 days after the last encorafenib dose were counted as treatment emergent and attributed to the last treatment taken. Events that occurred during the washout period (up to 28 days from the last treatment) between study periods were counted as treatment emergent and attributed to the previous treatment taken.
Time frame: Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline)
Population: All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (All Causalities) | 11 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (Treatment related) | 11 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with SAEs (All Causalities) | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with severe (including fatal) adverse events (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (All Causalities) | 11 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with severe (including fatal) adverse events (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (Treatment related) | 9 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with SAEs (All Causalities) | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with severe (including fatal) adverse events (All Causalities) | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (Treatment related) | 8 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with SAEs (All Causalities) | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (All Causalities) | 8 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (All Causalities) | 1 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (Treatment related) | 1 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with severe (including fatal) adverse events (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with SAEs (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with severe (including fatal) adverse events (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with SAEs (All Causalities) | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (Treatment related) | 5 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with AEs (All Causalities) | 5 Participants |
Secondary
Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities
Absolute values and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by protocol pre-defined categorization criterion. QTcF were derived using Fridericia's heart rate correction formula. For each period, triplicate ECGs were conducted predose on Day 1; all other ECG measurements were single ECGs. The baseline ECG value was the average of the triplicate ECG measurements collected before dose administration on Day 1. Changes from baseline were defined as the change between the postdose ECG measurement and the derived baseline ECG.
Time frame: Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline)
Population: All participants randomly assigned to a treatment sequence and who took at least 1 dose of encorafenib. Participants were analyzed according to the formulation they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QT INTERVAL (MSEC) Value >=500 msec | 0 Participants |
| 75 mg Encorafenib eMCC, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | PR INTERVAL (MSEC) value >= 300 msec or %Chg>=25/50% | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | PR INTERVAL (MSEC) value >= 300 msec or %Chg>=25/50% | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec | 0 Participants |
| 75mg Encorafenib eMCCL, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QT INTERVAL (MSEC) Value >=500 msec | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QT INTERVAL (MSEC) Value >=500 msec | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% | 0 Participants |
| 75mg Encorafenib CAP, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | PR INTERVAL (MSEC) value >= 300 msec or %Chg>=25/50% | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | PR INTERVAL (MSEC) value >= 300 msec or %Chg>=25/50% | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QT INTERVAL (MSEC) Value >=500 msec | 0 Participants |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 450 msec <= Value < 480 msec or 480 msec <= Value < 500 msec or Value > 500 msec | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QT INTERVAL (MSEC) Value >=500 msec | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QRS COMPLEX (MSEC) Value >=140 msec or %Chg>=50% | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | PR INTERVAL (MSEC) value >= 300 msec or %Chg>=25/50% | 0 Participants |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities | QTCF (MSEC) 30 msec <= Chg < 60 msec or Chg > 60 msec | 0 Participants |
Secondary
Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
t½ for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 4.691 hour | Standard Deviation 1.568 |
| 75mg Encorafenib eMCCL, Fasted | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 4.850 hour | Standard Deviation 2.0588 |
| 75mg Encorafenib CAP, Fasted | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 4.730 hour | Standard Deviation 1.7416 |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 4.710 hour | Standard Deviation 2.3714 |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 5.350 hour | Standard Deviation 2.0893 |
Secondary
Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
Tmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data as time of first occurrence.
Time frame: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Population: The PK parameter analysis population is defined as all participants randomized and treated who have at least 1 of the encorafenib plasma PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 75 mg Encorafenib eMCC, Fasted | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 1.00 hr |
| 75mg Encorafenib eMCCL, Fasted | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 1.00 hr |
| 75mg Encorafenib CAP, Fasted | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 1.5 hr |
| 75mg Encorafenib eMCC + 20 mg Rabeprazole, Fasted | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 1.25 hr |
| 75mg Encorafenib eMCCL + 20 mg Rabeprazole, Fasted | Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole | 1.00 hr |