THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

ViiV Healthcare47 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Healthy Subjects

Interventions

Maraviroc (Part 1)DRUG

300 mg twice daily x 5 days

Maraviroc (Part 2)DRUG

150 mg once daily x 10 days

Darunavir/cobicistat (Part 2)DRUG

800/150 mg once daily x 10 days

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Pfizer New Haven Clinical Research Unit

New Haven, Connecticut, United States

Outcomes

Primary Outcomes

Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc

AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc

AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10

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)

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.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Secondary Outcomes

Part 1: Average Plasma Concentration (Cavg) of Maraviroc

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.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 2: Average Plasma Concentration (Cavg) of Maraviroc

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.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10

Data from ClinicalTrials.gov

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Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10

Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose

Time frame: 12 hours post-dose on Day 5

Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose

Time frame: 24 hours post-dose on Day 10

Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc

Time frame: 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

Time frame: 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

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.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc

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.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc

Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.

Time frame: 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 Metabolites of Maraviroc

Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose

Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573.

Time frame: 12 hour post-dose on Day 5

Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Time frame: Baseline up to end of study (up to 6 days)

Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Time frame: Baseline up to end of study (up to 11 days)

Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities

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.

Time frame: Baseline up to Day 6

Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities

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.

Time frame: Baseline up to Day 11

Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities

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).

Time frame: Baseline up to Day 6

Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities

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).

Time frame: Baseline up to Day 11

Part 1: Number of Participants With Laboratory Abnormalities

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.

Time frame: Baseline up to Day 6

Part 2: Number of Participants With Laboratory Abnormalities

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.

Time frame: Baseline up to Day 11