Conditions: Healthy Subjects
Keywords: Maraviroc, CYP3A5, pharmacokinetics, pharmacogenomics
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: yes

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.

Arms:
arm 1: African-Americans with No CYP3A5\*1 alleles (poor metabolizer) arm 2: African-Americans with One CYP3A5\*1 allele (intermediate metabolizer) arm 3: African-Americans with Two CYP3A5\*1 alleles (extensive metabolizer) arm 4: Caucasians with No CYP3A5\*1 alleles (poor metabolizer)

Interventions: intervention 1: Maraviroc (Part 1) intervention 2: Maraviroc (Part 2) intervention 3: Darunavir/cobicistat (Part 2)
Intervention descriptions: intervention 1: 300 mg twice daily x 5 days intervention 2: 150 mg once daily x 10 days intervention 3: 800/150 mg once daily x 10 days

Protocol document: