THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC
Condition: Healthy Subjects
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Maraviroc (Part 1); Maraviroc (Part 2); Darunavir/cobicistat (Part 2)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 300 mg twice daily x 5 days; 150 mg once daily x 10 days; 800/150 mg once daily x 10 days
Other intervention name(s): Selzentry; Selzentry; Prezcobix
Intervention MeSH terms: Maraviroc; Darunavir; Cobicistat; Cobicistat mixture with darunavir
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Maraviroc, CYP3A5, pharmacokinetics, pharmacogenomics