THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 4/21/2016 |
| Start Date: | November 2015 |
| End Date: | March 2016 |
A Phase 1, Open-label, Parallel-group Study To Assess The Effect Of Cyp3a5 Genotype On The Pharmacokinetics Of Maraviroc And Cyp3a5-derived Metabolites With And Without Darunavir/Cobicistat In African-american And Caucasian Healthy Volunteers
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).
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).
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.
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.
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
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