THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

Phase 1

Completed

Conditions: Healthy Subjects

Interventions: Drug: Maraviroc (Part 1)
Drug: Maraviroc (Part 2)
Drug: Darunavir/cobicistat (Part 2)

Registration Number: NCT02625207

Lead Sponsor: ViiV Healthcare

Brief Summary: This will be an open-label, parallel group, multiple dose study in approximately 48 healthy male or female subjects of African American and Caucasian self-reported race, to assess the effect of CYP3A5 genotype on the PK of MVC and CYP3A5-derived metabolites. Maraviroc and CYP3A5-derived metabolite PK will also be compared between African-Americans and Caucasians in subjects carrying two copies of the dysfunctional CYP3A5 alleles (\*3, \*6, and/or \*7).

Detailed Description: This will be an open-label, parallel group, multiple dose study in approximately 48 healthy male or female subjects of African American and Caucasian self-reported race, to assess the effect of CYP3A5 genotype on the PK of MVC and CYP3A5-derived metabolites. Maraviroc and CYP3A5-derived metabolite PK will also be compared between African-Americans and Caucasians in subjects carrying two copies of the dysfunctional CYP3A5 alleles (\*3, \*6, and/or \*7).

Dysfunctional genetic variants for CYP3A5, CYP3A4 and SLCO1B1 will be genotyped for subjects who participate in the pre-screening. Subjects who meet the inclusion/exclusion criteria for study participation will be placed into the study cohorts based on race and the number of functional (\*1) and dysfunctional CYP3A5 alleles (\*3, \*6, and \*7) CYP3A5 alleles.

Cohort 1 (n=12; African-American): No CYP3A5\*1 alleles (poor metabolizer). Cohort 2 (n=12; African-American): One CYP3A5\*1 allele (intermediate metabolizer).

Cohort 3 (n=12; African-American): Two CYP3A5\*1 alleles (extensive metabolizer).

Cohort 4 (n=12; Caucasian): No CYP3A5\*1 alleles (poor metabolizer).

Study Treatments:

Part 1 Days 1-5: Maraviroc 300 mg BID in fasted state (AM dose only on Day 5). Part 2 (Cohorts 1 and 3 only) Days 1-10: Maraviroc 150 mg QD plus darunavir/cobicistat 800/150 mg QD with food.

Pharmacokinetics of MVC, PF-6857639, PF-6857640 and other hydroxylated metabolites with formation mediated by CYP3A5 (if present) will be assessed on Part 1, Day 5 and Part 2, Days 10-11. Blood samples will be collected for a full PK profile.

Subjects will be confined to the Clinical Research Unit (CRU) the day prior to dosing on Day 1 (Day 0) and discharged on Part 1, Day 6 and on Part 2, Day 11 (Cohorts 1 and 3 only). Subjects enrolled into Cohorts 1 and 3 may be confined to the CRU without the need to be discharged between Part 1 and Part 2.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs)
Healthy female subjects and/or male subjects of African-American/Black or Caucasian race

Exclusion Criteria

History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males
Treatment with an investigational drug within 30 days
Screening supine blood pressure <90 or >/=140 mm Hg (systolic) or <60 or >/= 90 mm Hg (diastolic), following at least 5 minutes of supine rest
Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication.
Use of tobacco- or nicotine-containing products in excess of the equivalent of 5 cigarettes per day
Subjects who have a CYP3A4*22 allele and/or have a SLCO1B1 *5 or *15 allele

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3	Maraviroc (Part 1)	African-Americans with Two CYP3A5\*1 alleles (extensive metabolizer)
Cohort 1	Maraviroc (Part 2)	African-Americans with No CYP3A5\*1 alleles (poor metabolizer)
Cohort 2	Maraviroc (Part 1)	African-Americans with One CYP3A5\*1 allele (intermediate metabolizer)
Cohort 3	Maraviroc (Part 2)	African-Americans with Two CYP3A5\*1 alleles (extensive metabolizer)
Cohort 1	Maraviroc (Part 1)	African-Americans with No CYP3A5\*1 alleles (poor metabolizer)
Cohort 3	Darunavir/cobicistat (Part 2)	African-Americans with Two CYP3A5\*1 alleles (extensive metabolizer)
Cohort 1	Darunavir/cobicistat (Part 2)	African-Americans with No CYP3A5\*1 alleles (poor metabolizer)
Cohort 4	Maraviroc (Part 1)	Caucasians with No CYP3A5\*1 alleles (poor metabolizer)

Primary Outcome Measures

Name	Time	Method
Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose.
Part 1: Metabolite to Parent Ratio for Area Under the Concentration-Time Curve From Time 0 to 12 Hours for Maraviroc and Its Metabolites (MRAUC12)	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	MRAUC12 is the ratio of AUC12 of maraviroc to AUC12 of maraviroc's metabolites. Metabolites of Maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. AUC12 is the area under the plasma concentration-time profile from time 0 to 12 hours post-dose.
Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10	AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.

Secondary Outcome Measures

Name	Time	Method
Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose	24 hours post-dose on Day 10
Part 1: Average Plasma Concentration (Cavg) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	Cavg is the average plasma concentration of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC \[0-12\]) divided by 12.
Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose	12 hours post-dose on Day 5
Part 2: Average Plasma Concentration (Cavg) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10	Cavg is the average plasma concentration of maraviroc during the 0 to 24 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC \[0-24\]) divided by 24.
Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	Cavg is the average plasma concentration of metabolites of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC \[0-12\]) divided by 12. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.
Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metabolites of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.
Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose	12 hour post-dose on Day 5	Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.
Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc	Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5	AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.
Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to end of study (up to 6 days)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. Treatment-emergent are events between first dose of study drug and up to 6 days that were absent before treatment or that worsened relative to pre-treatment state.
Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to end of study (up to 11 days)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. Treatment-emergent are events between first dose of study drug and up to 11 days that were absent before treatment or that worsened relative to pretreatment state.
Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities	Baseline up to Day 6	Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of less than (\<) 40 beats per minute (bpm) or greater than (\>)120 bpm, standing pulse rate of \<40 bpm or \>140 bpm, supine systolic blood pressure (SBP) and standing SBP of \<90 millimeter of mercury (mm Hg), greater than or equal to (\>=) 30 mm Hg, supine diastolic blood pressure (DBP) and standing DBP of \<50 mm Hg, \>=20 mm Hg.
Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities	Baseline up to Day 11	Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of \<40 bpm or \>120 bpm, standing pulse rate of \<40 bpm or \>140 bpm, supine SBP and standing SBP of \<90 mm Hg, \>=30 mm Hg, supine DBP and standing DBP of \<50 mm Hg, \>=20 mm Hg.
Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	Baseline up to Day 11	Criteria for ECG abnormalities: Maximum PR interval of \>=300 msec, maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent for baseline values of \>200 msec and \>=50 percent for baseline values of \<=200 msec for PR interval, maximum increase from baseline of \>=50 percent for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction).
Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	Baseline up to Day 6	Criteria for ECG abnormalities: Maximum PR interval of \>=300 milliseconds (msec), maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent for baseline values of \>200 msec and \>=50 percent for baseline values of less than or equal to (\<=) 200 msec for PR interval, maximum increase from baseline of \>=50 percent for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction).
Part 1: Number of Participants With Laboratory Abnormalities	Baseline up to Day 6	Criteria: Hemoglobin; hematocrit; red blood cell count: \<0.8\lower limit of normal, (LLN), mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume:\<0.9\LLN or \>1.1\* upper limit of normal (ULN), platelet: \<0.5\LLN or \>1.75\ULN, white blood cells \<0.6\LLN or \>1.5\ULN, lymphocyte; neutrophil: \<0.8\LLN or \>1.2\ULN, basophil; eosinophil; monocyte:\>1.2\ULN, bilirubin (total, direct, indirect) \>1.5\ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase:\>3.0\ULN, total protein; albumin:\<0.8\LLN or \>1.2\ULN; creatinine: \>1.3\ULN, uric acid\>1.2\ULN, sodium\<0.95\LLN or \>1.05\ULN, potassium; chloride; calcium; bicarbonate:\<0.9\LLN or \>1.1\ULN, glucose \<0.6\LLN or \>1.5\*ULN, urine specific gravity \<1.003, urine pH \<4.5 or \>8, urine glucose or ketones (qualitative) \>=1, urine protein; urine blood/hemoglobin \>=1, urobilinogen; bilirubin; nitrite; leukocyte esterase \>=1.
Part 2: Number of Participants With Laboratory Abnormalities	Baseline up to Day 11	Criteria: Hemoglobin; hematocrit; red blood cell count: \<0.8\LLN, mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume: \<0.9\LLN or \>1.1\ULN, platelet: \<0.5\LLN or \>1.75\ULN, white blood cells \<0.6\LLN or \>1.5\ULN, lymphocyte; neutrophil: \<0.8\LLN or \>1.2\ULN, basophil; eosinophil; monocyte: \>1.2\ULN, bilirubin (total, direct, indirect) \>1.5\ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase: \>3.0\ULN, total protein; albumin: \<0.8\LLN or \>1.2\ULN; creatinine: \>1.3\ULN, uric acid \>1.2\ULN, sodium\<0.95\LLN or \>1.05\ULN, potassium; chloride; calcium; bicarbonate:\<0.9\LLN or \>1.1\ULN, glucose \<0.6\LLN or \>1.5\ULN, urine specific gravity \<1.003, urine pH \<4.5 or \>8, urine glucose or ketones (qualitative) \>=1, urine protein; urine blood/hemoglobin \>=1, urobilinogen; bilirubin; nitrite; leukocyte esterase \>=1.