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THE EFFECT OF CYP3A5 GENOTYPE ON THE PHARMACOKINETICS OF MARAVIROC

1. März 2017 aktualisiert von: 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).

Studienübersicht

Status

Abgeschlossen

Bedingungen

Intervention / Behandlung

Detaillierte Beschreibung

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.

Studientyp

Interventionell

Einschreibung (Tatsächlich)

47

Phase

  • Phase 1

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienorte

  • Vereinigte Staaten
    • Connecticut
      • New Haven, Connecticut, Vereinigte Staaten, 06511
        • Pfizer New Haven Clinical Research Unit

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

18 Jahre bis 55 Jahre (Erwachsene)

Akzeptiert gesunde Freiwillige

Ja

Studienberechtigte Geschlechter

Alle

Beschreibung

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

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Behandlung
  • Zuteilung: Nicht randomisiert
  • Interventionsmodell: Parallele Zuordnung
  • Maskierung: Keine (Offenes Etikett)

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
Experimental: Cohort 1
African-Americans with No CYP3A5*1 alleles (poor metabolizer)
Arzneimittel: Maraviroc (Part 1)
300 mg twice daily x 5 days
Andere Namen:
  • Selbstzentriertheit
Arzneimittel: Maraviroc (Part 2)
150 mg once daily x 10 days
Andere Namen:
  • Selbstzentriertheit
Arzneimittel: Darunavir/cobicistat (Part 2)
800/150 mg once daily x 10 days
Andere Namen:
  • Prezcobix
Experimental: Cohort 2
African-Americans with One CYP3A5*1 allele (intermediate metabolizer)
Arzneimittel: Maraviroc (Part 1)
300 mg twice daily x 5 days
Andere Namen:
  • Selbstzentriertheit
Experimental: Cohort 3
African-Americans with Two CYP3A5*1 alleles (extensive metabolizer)
Arzneimittel: Maraviroc (Part 1)
300 mg twice daily x 5 days
Andere Namen:
  • Selbstzentriertheit
Arzneimittel: Maraviroc (Part 2)
150 mg once daily x 10 days
Andere Namen:
  • Selbstzentriertheit
Arzneimittel: Darunavir/cobicistat (Part 2)
800/150 mg once daily x 10 days
Andere Namen:
  • Prezcobix
Experimental: Cohort 4
Caucasians with No CYP3A5*1 alleles (poor metabolizer)
Arzneimittel: Maraviroc (Part 1)
300 mg twice daily x 5 days
Andere Namen:
  • Selbstzentriertheit

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc
Zeitfenster: 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
Zeitfenster: 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)
Zeitfenster: 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

Sekundäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Part 1: Average Plasma Concentration (Cavg) of Maraviroc
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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)
Zeitfenster: 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)
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

ViiV Healthcare

Mitarbeiter

Pfizer

Publikationen und hilfreiche Links

Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.

Allgemeine Veröffentlichungen

Nützliche Links

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn (Tatsächlich)

6. November 2015

Primärer Abschluss (Tatsächlich)

26. März 2016

Studienabschluss (Tatsächlich)

26. März 2016

Studienanmeldedaten

Zuerst eingereicht

20. Oktober 2015

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

8. Dezember 2015

Zuerst gepostet (Schätzen)

9. Dezember 2015

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

17. April 2017

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

1. März 2017

Zuletzt verifiziert

1. März 2017

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Schlüsselwörter

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

  • A4001110

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