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THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

1 de março de 2017 atualizado por: ViiV Healthcare

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).

Visão geral do estudo

Status

Concluído

Condições

Intervenção / Tratamento

Descrição detalhada

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.

Tipo de estudo

Intervencional

Inscrição (Real)

47

Estágio

  • Fase 1

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Locais de estudo

  • Estados Unidos
    • Connecticut
      • New Haven, Connecticut, Estados Unidos, 06511
        • Pfizer New Haven Clinical Research Unit

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

18 anos a 55 anos (Adulto)

Aceita Voluntários Saudáveis

Sim

Gêneros Elegíveis para o Estudo

Tudo

Descrição

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

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Tratamento
  • Alocação: Não randomizado
  • Modelo Intervencional: Atribuição Paralela
  • Mascaramento: Nenhum (rótulo aberto)

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Experimental: Cohort 1
African-Americans with No CYP3A5*1 alleles (poor metabolizer)
Medicamento: Maraviroc (Part 1)
300 mg twice daily x 5 days
Outros nomes:
  • Selzentry
Medicamento: Maraviroc (Part 2)
150 mg once daily x 10 days
Outros nomes:
  • Selzentry
Medicamento: Darunavir/cobicistat (Part 2)
800/150 mg once daily x 10 days
Outros nomes:
  • Prezcobix
Experimental: Cohort 2
African-Americans with One CYP3A5*1 allele (intermediate metabolizer)
Medicamento: Maraviroc (Part 1)
300 mg twice daily x 5 days
Outros nomes:
  • Selzentry
Experimental: Cohort 3
African-Americans with Two CYP3A5*1 alleles (extensive metabolizer)
Medicamento: Maraviroc (Part 1)
300 mg twice daily x 5 days
Outros nomes:
  • Selzentry
Medicamento: Maraviroc (Part 2)
150 mg once daily x 10 days
Outros nomes:
  • Selzentry
Medicamento: Darunavir/cobicistat (Part 2)
800/150 mg once daily x 10 days
Outros nomes:
  • Prezcobix
Experimental: Cohort 4
Caucasians with No CYP3A5*1 alleles (poor metabolizer)
Medicamento: Maraviroc (Part 1)
300 mg twice daily x 5 days
Outros nomes:
  • Selzentry

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc
Prazo: 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.
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
Prazo: 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.
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)
Prazo: 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.
Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5

Medidas de resultados secundários

Medida de resultado
Descrição da medida
Prazo
Part 1: Average Plasma Concentration (Cavg) of Maraviroc
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
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
Prazo: 12 hours post-dose on Day 5
12 hours post-dose on Day 5
Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose
Prazo: 24 hours post-dose on Day 10
24 hours post-dose on Day 10
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10
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
Prazo: 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. 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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5
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
Prazo: 12 hour post-dose on Day 5
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)
Prazo: Baseline up to end of study (up to 6 days)
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)
Prazo: Baseline up to end of study (up to 11 days)
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
Prazo: Baseline up to Day 6
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
Prazo: Baseline up to Day 11
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
Prazo: Baseline up to Day 6
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
Prazo: Baseline up to Day 11
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
Prazo: Baseline up to Day 6
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
Prazo: Baseline up to Day 11
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

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

ViiV Healthcare

Colaboradores

Pfizer

Publicações e links úteis

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Publicações Gerais

Links úteis

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo (Real)

6 de novembro de 2015

Conclusão Primária (Real)

26 de março de 2016

Conclusão do estudo (Real)

26 de março de 2016

Datas de inscrição no estudo

Enviado pela primeira vez

20 de outubro de 2015

Enviado pela primeira vez que atendeu aos critérios de CQ

8 de dezembro de 2015

Primeira postagem (Estimativa)

9 de dezembro de 2015

Atualizações de registro de estudo

Última Atualização Postada (Real)

17 de abril de 2017

Última atualização enviada que atendeu aos critérios de controle de qualidade

1 de março de 2017

Última verificação

1 de março de 2017

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • A4001110

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