Pharmacogenetics of Warfarin Induction and Inhibition

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Control - Warfarin only; Drug: Fluconazole - Warfarin; Drug: Rifampin - Warfarin

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: Interventional
• Enrollment (Actual): 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • Clinical and Translational Science Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.	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 Names: 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: Coumadin; Rifadin
Other: 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.	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 Names: 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: Coumadin; Rifadin
Other: 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.	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 Names: 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: Coumadin; Rifadin
Other: 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.	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 Names: 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: Coumadin; Rifadin
Other: 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.	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 Names: 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: Coumadin; Rifadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Warfarin Clearance.	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.

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Richard Brundage, PhD, University of Minnesota

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: January 29, 2010
• First Submitted That Met QC Criteria: October 4, 2011
• First Posted (Estimate): October 6, 2011

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Genetics; Healthy Volunteers; Drug Interactions; Warfarin; CYP2C9
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Anticoagulants; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Rifampin; Warfarin; Fluconazole
• Other Study ID Numbers: 0807M38361; P01GM032165-26 (U.S. NIH Grant/Contract)