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Pharmacogenetics of Warfarin Induction and Inhibition

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ClinicalTrials.gov Identifier: NCT01447511
Recruitment Status : Completed
First Posted : October 6, 2011
Results First Posted : August 18, 2014
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE January 29, 2010
First Posted Date  ICMJE October 6, 2011
Results First Submitted Date  ICMJE July 30, 2014
Results First Posted Date  ICMJE August 18, 2014
Last Update Posted Date November 14, 2018
Study Start Date  ICMJE May 2009
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 30, 2014)
Warfarin Clearance. [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 4, 2011)
To measure warfarin clearance. [ Time Frame: Over three 12-16 day study periods. ]
The magnitude of the warfarin-fluconazole drug interaction in healthy volunteers genotyped for CYP2C9*1/ *1, *1/*3 or *3/*3 alleles by measuring warfarin enantiomer clearance.
Change History Complete list of historical versions of study NCT01447511 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2011)
To measure prothrombin time. [ Time Frame: Over three 12-16 day study periods. ]
The magnitude of the warfarin-fluconazole drug interaction in healthy volunteers genotyped for CYP2C9*1/ *1, *1/*3 or *3/*3 alleles by measuring prothrombin time.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacogenetics of Warfarin Induction and Inhibition
Official Title  ICMJE Pharmacogenetics of Warfarin Induction and Inhibition
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: 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.
    Other Name: Coumadin
  • Drug: 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.
    Other Names:
    • Diflucan
    • Coumadin
  • Drug: 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.
    Other Names:
    • Rifadin
    • Coumadin
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Control - Warfarin only
    • Drug: Fluconazole - Warfarin
    • Drug: Rifampin - Warfarin
  • 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.
    Interventions:
    • Drug: Control - Warfarin only
    • Drug: Rifampin - Warfarin
  • 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.
    Interventions:
    • Drug: Control - Warfarin only
    • Drug: Fluconazole - Warfarin
    • Drug: Rifampin - Warfarin
  • 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.
    Interventions:
    • Drug: Control - Warfarin only
    • Drug: Fluconazole - Warfarin
    • Drug: Rifampin - Warfarin
  • 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.
    Interventions:
    • Drug: Control - Warfarin only
    • Drug: Fluconazole - Warfarin
    • Drug: Rifampin - Warfarin
Publications * Flora DR, Rettie AE, Brundage RC, Tracy TS. CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites. J Clin Pharmacol. 2017 Mar;57(3):382-393. doi: 10.1002/jcph.813. Epub 2016 Sep 22.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 12, 2013)
39
Original Estimated Enrollment  ICMJE
 (submitted: October 4, 2011)
21
Actual Study Completion Date  ICMJE June 2013
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01447511
Other Study ID Numbers  ICMJE 0807M38361
P01GM032165-26 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE National Institute of General Medical Sciences (NIGMS)
Investigators  ICMJE
Principal Investigator: Richard Brundage, PhD University of Minnesota
PRS Account University of Minnesota
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP