Clinical trial NCT02625207: THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: Maraviroc, CYP3A5, pharmacokinetics, pharmacogenomics
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2015-12-09
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
measure: Part 1: Metabolite to Parent Ratio for Area Under the Concentration-Time Curve From Time 0 to 12 Hours for Maraviroc and Its Metabolites (MRAUC12)
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
Secondary outcomes:
measure: Part 1: Average Plasma Concentration (Cavg) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 2: Average Plasma Concentration (Cavg) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
measure: Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose
timeFrame: 12 hours post-dose on Day 5
measure: Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose
timeFrame: 24 hours post-dose on Day 10
measure: Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
measure: Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metabolites of Maraviroc
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
measure: Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose
timeFrame: 12 hour post-dose on Day 5
measure: Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to end of study (up to 6 days)
measure: Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to end of study (up to 11 days)
measure: Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: Baseline up to Day 6
measure: Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: Baseline up to Day 11
measure: Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
timeFrame: Baseline up to Day 6
measure: Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
timeFrame: Baseline up to Day 11
measure: Part 1: Number of Participants With Laboratory Abnormalities
timeFrame: Baseline up to Day 6
measure: Part 2: Number of Participants With Laboratory Abnormalities
timeFrame: Baseline up to Day 11
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Pfizer New Haven Clinical Research Unit
state: Connecticut
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Vourvahis M, McFadyen L, Nepal S, Valluri SR, Fang A, Fate GD, Wood LS, Marshall JC, Chan PLS, Nedderman A, Haynes J, Savage ME, Clark A, Smith KY, Heera J. No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects. J Clin Pharmacol. 2019 Jan;59(1):139-152. doi: 10.1002/jcph.1306. Epub 2018 Sep 7.