THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

ViiV Healthcare

Status and phase: Completed; Phase 1

Conditions: Healthy Subjects

Treatments: Drug: Maraviroc (Part 1); Drug: Darunavir/cobicistat (Part 2); Drug: Maraviroc (Part 2)

Study type: Interventional

Funder types: Industry

Identifiers

NCT02625207

A4001110

Details and patient eligibility

About

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).

Full 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.

Enrollment: 47 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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47 participants in 4 patient groups

Cohort 1

Experimental group

Description:

African-Americans with No CYP3A5\*1 alleles (poor metabolizer)

Treatment:

Drug: Maraviroc (Part 2)

Drug: Darunavir/cobicistat (Part 2)

Drug: Maraviroc (Part 1)

Cohort 2

Experimental group

Description:

African-Americans with One CYP3A5\*1 allele (intermediate metabolizer)

Treatment:

Drug: Maraviroc (Part 1)

Cohort 3

Experimental group

Description:

African-Americans with Two CYP3A5\*1 alleles (extensive metabolizer)

Treatment:

Drug: Maraviroc (Part 2)

Drug: Darunavir/cobicistat (Part 2)

Drug: Maraviroc (Part 1)

Cohort 4

Experimental group

Description:

Caucasians with No CYP3A5\*1 alleles (poor metabolizer)

Treatment:

Drug: Maraviroc (Part 1)