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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc
研究概览
简要总结
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).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Cohort 1
African-Americans with No CYP3A5*1 alleles (poor metabolizer)
干预措施: Maraviroc (Part 1) (Drug)
Cohort 1
African-Americans with No CYP3A5*1 alleles (poor metabolizer)
干预措施: Maraviroc (Part 2) (Drug)
Cohort 1
African-Americans with No CYP3A5*1 alleles (poor metabolizer)
干预措施: Darunavir/cobicistat (Part 2) (Drug)
Cohort 2
African-Americans with One CYP3A5*1 allele (intermediate metabolizer)
干预措施: Maraviroc (Part 1) (Drug)
Cohort 3
African-Americans with Two CYP3A5*1 alleles (extensive metabolizer)
干预措施: Maraviroc (Part 1) (Drug)
Cohort 3
African-Americans with Two CYP3A5*1 alleles (extensive metabolizer)
干预措施: Maraviroc (Part 2) (Drug)
Cohort 3
African-Americans with Two CYP3A5*1 alleles (extensive metabolizer)
干预措施: Darunavir/cobicistat (Part 2) (Drug)
Cohort 4
Caucasians with No CYP3A5*1 alleles (poor metabolizer)
干预措施: Maraviroc (Part 1) (Drug)
结局指标
主要结局
Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc
时间窗: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose.
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)
时间窗: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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.
Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc
时间窗: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.
次要结局
- Part 1: Average Plasma Concentration (Cavg) of Maraviroc(Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5)
- 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 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 2: Average Plasma Concentration (Cavg) of Maraviroc(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 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 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc(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(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(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(12 hour 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: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc(Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5)
- Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(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)(Baseline up to end of study (up to 11 days))
- Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities(Baseline up to Day 6)
- Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities(Baseline up to Day 11)
- Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities(Baseline up to Day 11)
- Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities(Baseline up to Day 6)
- Part 1: Number of Participants With Laboratory Abnormalities(Baseline up to Day 6)
- Part 2: Number of Participants With Laboratory Abnormalities(Baseline up to Day 11)