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Pharmacogenetics of Warfarin Induction and Inhibition

15. oktober 2018 opdateret af: University of Minnesota

This research study will help determine how a person's genetic makeup affects their response to drugs, the ability of the body to break down drugs, and their potential to experience an interaction between drugs. The investigators are investigating the drug interactions with the commonly used anticoagulant drug called warfarin. Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots such as deep vein thrombosis, heart attacks, and strokes. The investigators chose warfarin for this study because it is a commonly used drug and must be monitored closely to avoid side effects. The investigators are interested in studying whether individuals with certain genetic profiles react differently to warfarin when it is combined with other drugs. This research is being done to see if certain genetic profiles require us to adjust warfarin doses differently than is needed for the general population. Genetic profiles of subjects are determined from their participation in the Pharmacogenetics Registry study (investigator Richard Brundage, University of Minnesota).

The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive interaction.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

The research question is: How does CYP2C9 genotype modify warfarin drug interactions?

People differ in their genetic makeup. This includes differences in genes involved in drug metabolism, transport, and effect in the body. People with certain genetic profiles produce altered enzymes, transporters, and receptors that may respond in different ways to drugs. Altered enzymes cause some drugs to be broken down at a different rate than normal. As a result, drug concentrations build up in the blood, and increase the risk of side effects. Furthermore, when two drugs are taken together, the possibility exists for the drugs to interact, with one drug causing a change in the metabolism of the other or both of the drugs. It is not known whether people with an altered genetic makeup also have an altered experience with drug interactions. Altered drug transporters can affect the absorption and elimination of drugs as compared to normal causing differences in how long the drug stays in the body. Finally, altered drug receptors can respond differently to drugs and, thus, produce altered desired or undesired effects.

In this study, the investigators will be investigating the drug interactions with the commonly used anticoagulant drug warfarin in subjects with five different CYP2C9 genotypes. The CYP2C9 genotype is particularly important because this drug metabolizing enzyme governs the metabolic clearance of the more potent chemical entity (the S-enantiomer) of the drug. Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots such as deep vein thrombosis, myocardial infarction, and strokes. The investigators chose warfarin for this study because it is a commonly used drug and must be monitored closely to avoid side effects. The investigators are interested in studying whether individuals with certain genetic alleles of the CYP2C9 genotype react differently to warfarin when it is combined with an antifungal (fluconazole) that inhibits CYP2C9-mediated metabolism and an antibiotic (rifampin) that induces CYP2C9-mediated metabolism. This research is being done to see if certain genetic profiles require us to adjust warfarin doses differently than is needed for the general population.

The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive interaction.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

39

Fase

  • Ikke anvendelig

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Forenede Stater
    • Minnesota
      • Minneapolis, Minnesota, Forenede Stater, 55414
        • Clinical and Translational Science Institute

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 60 år (Voksen)

Tager imod sunde frivillige

Ja

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion Criteria:

  • Subjects will be 18-60 years old.
  • Women of child bearing age must be willing to use measures to avoid conception during the study period.
  • Subjects must agree not to take any known substrates, inhibitors, inducers or activators of either CYP2C9 or CYP3A4 from 1 week prior to the start of each study through the last day of study.

Exclusion Criteria:

  • Current cigarette smoker
  • Abnormal renal, liver function tests, physical exam, or recent history of hepatic, renal, gastrointestinal or neoplastic disease.
  • Allergy to warfarin, fluconazole or rifampin and other chemically related drugs.
  • Recent ingestion (< 1 week) of any medication known to be metabolized by or alter CYP2C9 or CYP3A4 activity.
  • A positive pregnancy test at the time of the pharmacokinetic study.
  • Lab tests indicative of abnormal blood clotting capacity.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Grundvidenskab
  • Tildeling: Ikke-randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Andet: CYP2C9*1/*1 Genotype
This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
Medicin: Control - Warfarin only
A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.
Andre navne:
  • Coumadin
Medicin: Fluconazole - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Diflucan
  • Coumadin
Medicin: Rifampin - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Coumadin
  • Rifadin
Andet: CYP2C9*1B/*1B Haplotype
Individuals with the CYP2C9*1B/*1B haplotype have two CYP2C9*1B alleles and participated in the following interventions: Control - Warfarin only and Rifampin - Warfarin.
Medicin: Control - Warfarin only
A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.
Andre navne:
  • Coumadin
Medicin: Rifampin - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Coumadin
  • Rifadin
Andet: CYP2C9*1/*3 Genotype
Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
Medicin: Control - Warfarin only
A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.
Andre navne:
  • Coumadin
Medicin: Fluconazole - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Diflucan
  • Coumadin
Medicin: Rifampin - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Coumadin
  • Rifadin
Andet: CYP2C9*2/*3 Genotype
Individuals with the CYP2C9*2/*3 genotype have one *2 and one *3 allele and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
Medicin: Control - Warfarin only
A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.
Andre navne:
  • Coumadin
Medicin: Fluconazole - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Diflucan
  • Coumadin
Medicin: Rifampin - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Coumadin
  • Rifadin
Andet: CYP2C9*3/*3 Genotype
Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following interventions: Control - Warfarin only, Fluconazole - Warfarin, and Rifampin - Warfarin.
Medicin: Control - Warfarin only
A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.
Andre navne:
  • Coumadin
Medicin: Fluconazole - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Diflucan
  • Coumadin
Medicin: Rifampin - Warfarin
A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Andre navne:
  • Coumadin
  • Rifadin

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Warfarin Clearance.
Tidsramme: Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
Warfarin enantiomer (S-warfarin and R-warfarin) clearance was measured in healthy volunteers genotyped for CYP2C9*1/*1, CYP2C9*1B/*1B, CYP2C9*1/*3, CYP2C9*2/*3 and CYP2C9*3/*3 to determine the magnitude of the warfarin-fluconazole (inhibition) and warfarin-rifampin (induction) drug interactions.
Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

University of Minnesota

Samarbejdspartnere

National Institute of General Medical Sciences (NIGMS)

Efterforskere

  • Ledende efterforsker: Richard Brundage, PhD, University of Minnesota

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. maj 2009

Primær færdiggørelse (Faktiske)

1. juni 2013

Studieafslutning (Faktiske)

1. juni 2013

Datoer for studieregistrering

Først indsendt

29. januar 2010

Først indsendt, der opfyldte QC-kriterier

4. oktober 2011

Først opslået (Skøn)

6. oktober 2011

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

14. november 2018

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

15. oktober 2018

Sidst verificeret

1. oktober 2018

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 0807M38361
  • P01GM032165-26 (U.S. NIH-bevilling/kontrakt)

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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