THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

Healthy Subjects Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02625207
• Other study ID #: A4001110
• Status: Completed
• Phase: Phase 1
• First received: October 20, 2015
• Last updated: April 11, 2016
• Start date: November 2015
• Est. completion date: March 2016

Study information

• Verified date: April 2016
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• Maraviroc (Part 1)
300 mg twice daily x 5 days
• Maraviroc (Part 2)
150 mg once daily x 10 days
• Darunavir/cobicistat (Part 2)
800/150 mg once daily x 10 days

Locations

Country	Name	City	State
United States	Pfizer New Haven Clinical Research Unit	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maraviroc AUC	Maraviroc area under the time plasma concentration time curve (AUC): AUC12 (Part 1), AUC24 (Part 2) and AUCparent/metabolite ratios	15 days	No
Secondary	Maraviroc and metabolite Cavg	Maraviroc, PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present) average plasma concentration (Cavg)	15 days	No
Secondary	Maraviroc and metabolite Cmax	Maraviroc, PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present) peak plasma concentration (Cmax)	15 days	No
Secondary	Maraviroc and metabolite Tmax	Maraviroc, PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present)time to Cmax (Tmax)	15 days	No
Secondary	Maraviroc and metabolite C12h	Maraviroc, PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present) plasma concentration at 12 hours (C12h; Part 1)	15 days	No
Secondary	Maraviroc and metabolite C24h	Maraviroc, PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present) plasma concentration at 24 hours (C24h; Part 2)	15 days	No
Secondary	Maraviroc metabolite AUC	PF-6857639, PF-6857640 and other hydroxylated metabolite with formation mediated by CYP3A5 (if present) area under the time plasma concentration time curve (AUC): AUC12 (Part 1), AUC24 (Part 2) and AUCparent/metabolite ratios	15 days	No
Secondary	Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Safety and tolerability assessed by reported adverse events, vital signs, 12-lead electrocardiogram (ECG) and laboratory safety assessments	15 days	Yes

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