Pharmacogenetics of Warfarin Induction and Inhibition

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01447511
First received: January 29, 2010
Last updated: July 30, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention
Warfarin
Drug Interactions
Drug: Control - Warfarin only
Drug: Fluconazole - Warfarin
Drug: Rifampin - Warfarin

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Pharmacogenetics of Warfarin Induction and Inhibition

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Warfarin Clearance. [ Time Frame: Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods. ] [ Designated as safety issue: No ]
    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.


Enrollment: 39
Study Start Date: May 2009
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
CYP2C9*1/*1 Genotype 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
CYP2C9*1B/*1B Haplotype 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: 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
CYP2C9*1/*3 Genotype 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
CYP2C9*2/*3 Genotype 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
CYP2C9*3/*3 Genotype 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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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 CYP3A activity.
  • A positive pregnancy test at the time of the pharmacokinetic study.
  • Lab tests indicative of abnormal blood clotting capacity.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01447511

Locations
United States, Minnesota
Clinical and Translational Science Institute
Minneapolis, Minnesota, United States, 55414
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Investigators
Principal Investigator: Richard Brundage, PhD University of Minnesota - Clinical and Translational Science Institute
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01447511     History of Changes
Other Study ID Numbers: 0807M38361, P01GM032165-26
Study First Received: January 29, 2010
Results First Received: July 30, 2014
Last Updated: July 30, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
healthy volunteers
drug interactions
warfarin
normal controls
genetics
CYP2C9

Additional relevant MeSH terms:
Fluconazole
Rifampin
Warfarin
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antitubercular
Anti-Bacterial Agents
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Anticoagulants
Hematologic Agents

ClinicalTrials.gov processed this record on August 28, 2014