Healthy
Conditions
Brief summary
The purpose of this study is to understand if a strong CYP3A4 inhibitor (itraconazole) affects how ARV-471 is processed and eliminated in healthy adults. All participants in this study will receive one dose of ARV-471 alone by mouth in Period 1. In Period 2, everyone will receive itraconazole by mouth once a day for multiple days. Participants will also receive one dose of ARV-471 by mouth. The levels of ARV-471 in Period 1 will be compared to the levels of ARV-471 in Period 2 to determine if the CYP3A4 inhibitor affects how ARV-471 is processed differently in healthy adults.
Interventions
DRUGvepdegestrant
Participants will receive a single dose of vepdegestrant by mouth in Period 1 and Period 2, with a washout period of at least 10 days between doses of vepdegestrant
DRUGItraconazole
Participants will receive itraconazole by mouth once a day for 11 days in Period 2.
Sponsors
Pfizer
Arvinas Estrogen Receptor, Inc.
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female participants of non-childbearing potential who are overtly healthy as determined by medical evaluation including medical history, physical exam, laboratory tests, vital signs and standard 12-lead ECGs and are between the ages of 18 and 65 years, inclusive at the time of signing the informed consent document. * Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight \>50 kg. * Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study. * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). * Pregnant female participants, breastfeeding female participants, female participants of childbearing potential. * Male participants with partners currently pregnant; male participants who are unwilling or unable to use a highly effective method of contraception. * Use of prescription or non-prescription medications, including vitamins, herbal and dietary supplements, grapefruit/grapefruit containing products, and Seville orange/Seville orange containing products within 7 days prior to the first dose of study intervention with the exception of: Moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives (whichever is longer) prior to the first dose of study intervention. Moderate/potent CYP3A inhibitors which are prohibited within 14 days or 5 half lives (whichever is longer) prior to the first dose of study intervention. * Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). * A positive urine drug test or alcohol breath test at discretion of investigator. * Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. * Standard 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. * Aspartate transaminase or alanine aminotransferase level ≥ 1.0 × upper limit of normal. * Total bilirubin level \>1.0 × upper limit of normal; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ upper limit of normal. * History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. * History of use of tobacco or nicotine-containing products in excess of the equivalent of 5 cigarettes/day or 2 chews of tobacco/day. * Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. * Known hypersensitivity or previous adverse events associated with azole antifungals or any of the formulation components of ARV-471. * History of sensitivity to heparin or heparin induced thrombocytopenia. * Estimated glomerular filtration rate \<60 mL/min/1.73m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of ARV-471. AUCinf was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. |
| Maximum Observed Plasma Concentration (Cmax) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | Cmax was defined as maximum plasma concentration. Cmax of ARV-471 was observed directly from data. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to 120 Hours (AUC120) of ARV-473 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose | ARV-473 was the epimer of ARV-471. AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method. |
| Cmax of ARV-473 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | ARV-473 was the epimer of ARV-471. Cmax was defined as maximum plasma concentration. Cmax of ARV-473 was observed directly from data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Clearance After Oral Dose (CL/F) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | CL/F was defined as apparent oral clearance and calculated by dose/AUCinf. AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time. |
| Apparent Volume of Distribution After Oral Dose (Vz/F) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | Vz/F was defined as apparent volume of distribution calculated by dose/(AUCinf \* kel). AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time and kel was defined as the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| AUClast of ARV-473 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | ARV-473 was the epimer of ARV-471. AUClast was defined as area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method. |
| Tmax of ARV-473 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | ARV-473 was the epimer of ARV-471. Time for Cmax of ARV-473 was observed directly from data as time of first occurrence. |
| Area Under the Plasma Concentration Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | AUClast was defined as area under the plasma concentrationtime profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method. |
| Number of Participants With Clinical Laboratory Abnormalities | Baseline (Period 1 Day -1) up to Period 2 Day 12 (19 days) | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid, cystatinC); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (dipstick \[decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, nitrites, leukoesterase, urobilinogen, bilirubin\], microscopy. Abnormality was determined at the investigator's discretion. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Baseline (Period 1 Day 1) up to Period 2 Day 5 (11 days) | Vital signs (blood pressure and pulse rate) were obtained with participant following at least a 5-minute rest in a supine position. Clinical significance of vital signs was determined at the investigator's discretion. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline (Period 1 Day 1) up to Period 2 Day 12 (18 days) | ECG abnormalities criteria include a) a postdose QTc corrected using Fridericia's formula (QTcF) increased by ≥60 millisecond (ms) from the baseline and the absolute QTcF value \>450 ms; or b) an absolute QTcF value ≥500 ms for any scheduled ECG. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose (Day 1) up to 35 days after the last dose of study intervention (up to 52 days) | An AE is any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship with the study intervention. SAE is defined as one of the following: is fatal or life threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs. |
| AUC120 of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose | AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method. |
| Time for Cmax (Tmax) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | Time for Cmax of ARV-471 was observed directly from data as time of first occurrence. |
| Terminal Half-Life (t1/2) of ARV-471 | Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose | Terminal half-life (t1/2) was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
Countries
Belgium
Participant flow
Pre-assignment details
The study consisted of 2 periods in a single fixed sequence. A total of 12 participants were screened and enrolled into the study. All enrolled participants were treated and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received a single dose of ARV-471 (PF-07850327) 200 milligram (mg) on Period 1 Day 1. After completion of Period 1, participants received 200 mg itraconazole once daily on Period 2 Days 1-4 and 6-11. On Period 2 Day 5, participants received a single dose of Itraconazole 200 mg first, immediately followed by a single dose of ARV-471 200 mg. Following Period 1, a washout period of at least 10 days must occur between the 2 single doses of ARV-471. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 41.33 Years STANDARD_DEVIATION 11.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 2 / 12 | 3 / 12 | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) of ARV-471
AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of ARV-471. AUCinf was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 pharmacokinetic (PK) parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) of ARV-471 | 18960 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 23 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) of ARV-471 | 32020 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 24 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed AUCinf was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [157.66, 180.94]
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to 120 Hours (AUC120) of ARV-473
ARV-473 was the epimer of ARV-471. AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Area Under the Plasma Concentration-Time Profile From Time 0 to 120 Hours (AUC120) of ARV-473 | 4734 ng*hr/mL | Geometric Coefficient of Variation 30 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Area Under the Plasma Concentration-Time Profile From Time 0 to 120 Hours (AUC120) of ARV-473 | 7668 ng*hr/mL | Geometric Coefficient of Variation 28 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed AUC120 was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [148.7, 176.47]
Primary
Cmax of ARV-473
ARV-473 was the epimer of ARV-471. Cmax was defined as maximum plasma concentration. Cmax of ARV-473 was observed directly from data.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Cmax of ARV-473 | 56.37 ng/mL | Geometric Coefficient of Variation 26 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Cmax of ARV-473 | 86.31 ng/mL | Geometric Coefficient of Variation 27 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed Cmax was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [138.51, 169.3]
Primary
Maximum Observed Plasma Concentration (Cmax) of ARV-471
Cmax was defined as maximum plasma concentration. Cmax of ARV-471 was observed directly from data.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Maximum Observed Plasma Concentration (Cmax) of ARV-471 | 517.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Maximum Observed Plasma Concentration (Cmax) of ARV-471 | 788.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed Cmax was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [136.9, 169.18]
Secondary
Apparent Clearance After Oral Dose (CL/F) of ARV-471
CL/F was defined as apparent oral clearance and calculated by dose/AUCinf. AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Apparent Clearance After Oral Dose (CL/F) of ARV-471 | 10.54 liter per hour (L/hr) | Geometric Coefficient of Variation 23 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Apparent Clearance After Oral Dose (CL/F) of ARV-471 | 6.245 liter per hour (L/hr) | Geometric Coefficient of Variation 24 |
Secondary
Apparent Volume of Distribution After Oral Dose (Vz/F) of ARV-471
Vz/F was defined as apparent volume of distribution calculated by dose/(AUCinf \* kel). AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time and kel was defined as the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Apparent Volume of Distribution After Oral Dose (Vz/F) of ARV-471 | 645.6 liter (L) | Geometric Coefficient of Variation 29 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Apparent Volume of Distribution After Oral Dose (Vz/F) of ARV-471 | 549.5 liter (L) | Geometric Coefficient of Variation 20 |
Secondary
Area Under the Plasma Concentration Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of ARV-471
AUClast was defined as area under the plasma concentrationtime profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Area Under the Plasma Concentration Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of ARV-471 | 16730 ng*hr/mL | Geometric Coefficient of Variation 24 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Area Under the Plasma Concentration Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of ARV-471 | 28710 ng*hr/mL | Geometric Coefficient of Variation 21 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed AUClast was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [159.96, 184.15]
Secondary
AUC120 of ARV-471
AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | AUC120 of ARV-471 | 16730 ng*hr/mL | Geometric Coefficient of Variation 24 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | AUC120 of ARV-471 | 26400 ng*hr/mL | Geometric Coefficient of Variation 20 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed AUC120 was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [146.51, 169.95]
Secondary
AUClast of ARV-473
ARV-473 was the epimer of ARV-471. AUClast was defined as area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | AUClast of ARV-473 | 4734 ng*hr/mL | Geometric Coefficient of Variation 30 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | AUClast of ARV-473 | 9129 ng*hr/mL | Geometric Coefficient of Variation 31 |
Comparison: ARV-471 administered alone as Reference, ARV-471 administered after multiple doses of itraconazole as Test. Natural log transformed AUClast was analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [178.86, 207.94]
Secondary
Number of Participants With Clinical Laboratory Abnormalities
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid, cystatinC); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (dipstick \[decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, nitrites, leukoesterase, urobilinogen, bilirubin\], microscopy. Abnormality was determined at the investigator's discretion.
Time frame: Baseline (Period 1 Day -1) up to Period 2 Day 12 (19 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: ARV-471 200 mg | Number of Participants With Clinical Laboratory Abnormalities | 4 Participants |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Clinical Laboratory Abnormalities | 1 Participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs (blood pressure and pulse rate) were obtained with participant following at least a 5-minute rest in a supine position. Clinical significance of vital signs was determined at the investigator's discretion.
Time frame: Baseline (Period 1 Day 1) up to Period 2 Day 5 (11 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: ARV-471 200 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
Secondary
Number of Participants With Electrocardiogram (ECG) Abnormalities
ECG abnormalities criteria include a) a postdose QTc corrected using Fridericia's formula (QTcF) increased by ≥60 millisecond (ms) from the baseline and the absolute QTcF value \>450 ms; or b) an absolute QTcF value ≥500 ms for any scheduled ECG.
Time frame: Baseline (Period 1 Day 1) up to Period 2 Day 12 (18 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: ARV-471 200 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship with the study intervention. SAE is defined as one of the following: is fatal or life threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs.
Time frame: From the first dose (Day 1) up to 35 days after the last dose of study intervention (up to 52 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent AEs | 2 Participants |
| Period 1: ARV-471 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent SAEs | 0 Participants |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent AEs | 3 Participants |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent SAEs | 0 Participants |
| ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent AEs | 2 Participants |
| ARV-471 200 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent SAEs | 0 Participants |
Secondary
Terminal Half-Life (t1/2) of ARV-471
Terminal half-life (t1/2) was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Period 1: ARV-471 200 mg | Terminal Half-Life (t1/2) of ARV-471 | 42.64 hour | Standard Deviation 4.08 |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Terminal Half-Life (t1/2) of ARV-471 | 61.57 hour | Standard Deviation 9.1196 |
Secondary
Time for Cmax (Tmax) of ARV-471
Time for Cmax of ARV-471 was observed directly from data as time of first occurrence.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Period 1: ARV-471 200 mg | Time for Cmax (Tmax) of ARV-471 | 6.00 hour |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Time for Cmax (Tmax) of ARV-471 | 6.00 hour |
Secondary
Tmax of ARV-473
ARV-473 was the epimer of ARV-471. Time for Cmax of ARV-473 was observed directly from data as time of first occurrence.
Time frame: Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose
Population: Analysis population included all participants who received at least 1 dose of ARV-471 and/or itraconazole and had at least 1 of the ARV-471 or ARV-473 PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Period 1: ARV-471 200 mg | Tmax of ARV-473 | 24.0 hour |
| Period 2: ARV-471 200 mg + Itraconazole 200 mg | Tmax of ARV-473 | 35.9 hour |