THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

Study Overview
=================
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.

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

Conditions
-----------------
Healthy Subjects

Intervention / Treatment
-----------------
* Drug: Maraviroc (Part 1)
* Drug: Maraviroc (Part 2)
* Drug: Darunavir/cobicistat (Part 2)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>African-Americans with No CYP3A5*1 alleles (poor metabolizer) | Drug: Maraviroc (Part 1)<br>* 300 mg twice daily x 5 days<br>* Other names: Selzentry;Drug: Maraviroc (Part 2)<br>* 150 mg once daily x 10 days<br>* Other names: Selzentry;Drug: Darunavir/cobicistat (Part 2)<br>* 800/150 mg once daily x 10 days<br>* Other names: Prezcobix;|
| Experimental: Cohort 2<br>African-Americans with One CYP3A5*1 allele (intermediate metabolizer) | Drug: Maraviroc (Part 1)<br>* 300 mg twice daily x 5 days<br>* Other names: Selzentry;|
| Experimental: Cohort 3<br>African-Americans with Two CYP3A5*1 alleles (extensive metabolizer) | Drug: Maraviroc (Part 1)<br>* 300 mg twice daily x 5 days<br>* Other names: Selzentry;Drug: Maraviroc (Part 2)<br>* 150 mg once daily x 10 days<br>* Other names: Selzentry;Drug: Darunavir/cobicistat (Part 2)<br>* 800/150 mg once daily x 10 days<br>* Other names: Prezcobix;|
| Experimental: Cohort 4<br>Caucasians with No CYP3A5*1 alleles (poor metabolizer) | Drug: Maraviroc (Part 1)<br>* 300 mg twice daily x 5 days<br>* Other names: Selzentry;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc | AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 | 
| 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) | MRAUC12 is the ratio of AUC12 of maraviroc to AUC12 of maraviroc's metabolites. Metabolites of Maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. AUC12 is the area under the plasma concentration-time profile from time 0 to 12 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Average Plasma Concentration (Cavg) of Maraviroc | Cavg is the average plasma concentration of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 2: Average Plasma Concentration (Cavg) of Maraviroc | Cavg is the average plasma concentration of maraviroc during the 0 to 24 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC [0-24]) divided by 24. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 | 
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc |  | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc |  | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 | 
| Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose |  | 12 hours post-dose on Day 5 | 
| Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose |  | 24 hours post-dose on Day 10 | 
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc |  | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc |  | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 | 
| Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc | Cavg is the average plasma concentration of metabolites of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 | 
| Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | 12 hour post-dose on Day 5 | 
| Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 6 days that were absent before treatment or that worsened relative to pre-treatment state. | Baseline up to end of study (up to 6 days) | 
| Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 11 days that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to end of study (up to 11 days) | 
| Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of less than (<) 40 beats per minute (bpm) or greater than (>)120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine systolic blood pressure (SBP) and standing SBP of <90 millimeter of mercury (mm Hg), greater than or equal to (>=) 30 mm Hg, supine diastolic blood pressure (DBP) and standing DBP of <50 mm Hg, >=20 mm Hg. | Baseline up to Day 6 | 
| Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of <40 bpm or >120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine SBP and standing SBP of <90 mm Hg, >=30 mm Hg, supine DBP and standing DBP of <50 mm Hg, >=20 mm Hg. | Baseline up to Day 11 | 
| Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 milliseconds (msec), maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of less than or equal to (<=) 200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Baseline up to Day 6 | 
| Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 msec, maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of <=200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Baseline up to Day 11 | 
| Part 1: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*lower limit of normal, (LLN), mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume:<0.9*LLN or >1.1* upper limit of normal (ULN), platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte:>1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase:>3.0*ULN, total protein; albumin:<0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid>1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Baseline up to Day 6 | 
| Part 2: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*LLN, mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume: <0.9*LLN or >1.1*ULN, platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte: >1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase: >3.0*ULN, total protein; albumin: <0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid >1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Baseline up to Day 11 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Maraviroc, CYP3A5, pharmacokinetics, pharmacogenomics