Pharmacogenetics of Warfarin Induction and Inhibition

NCT01447511 | Completed Results

• 2 other identifiers: 0807M38361P01GM032165-26
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Drug Interactions; Warfarin; Genetics; CYP2C9; Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• 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.

Study Arms (5)

CYP2C9*1/*1 Genotype

OTHER

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; Drug: Fluconazole - Warfarin; Drug: Rifampin - Warfarin

CYP2C9*1B/*1B Haplotype

OTHER

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; Drug: Rifampin - Warfarin

CYP2C9*1/*3 Genotype

OTHER

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; Drug: Fluconazole - Warfarin; Drug: Rifampin - Warfarin

CYP2C9*2/*3 Genotype

OTHER

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; Drug: Fluconazole - Warfarin; Drug: Rifampin - Warfarin

CYP2C9*3/*3 Genotype

OTHER

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; Drug: Fluconazole - Warfarin; Drug: Rifampin - Warfarin

Interventions

Control - Warfarin only DRUG

A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.

Also known as: Coumadin

CYP2C9*1/*1 Genotype; CYP2C9*1/*3 Genotype; CYP2C9*1B/*1B Haplotype; CYP2C9*2/*3 Genotype; CYP2C9*3/*3 Genotype

Fluconazole - Warfarin DRUG

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.

Also known as: Diflucan, Coumadin

CYP2C9*1/*1 Genotype; CYP2C9*1/*3 Genotype; CYP2C9*2/*3 Genotype; CYP2C9*3/*3 Genotype

Rifampin - Warfarin DRUG

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.

Also known as: Rifadin, Coumadin

CYP2C9*1/*1 Genotype; CYP2C9*1/*3 Genotype; CYP2C9*1B/*1B Haplotype; CYP2C9*2/*3 Genotype; CYP2C9*3/*3 Genotype

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Minnesota: lead
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (1)

Clinical and Translational Science Institute

Minneapolis, Minnesota, 55414, United States

Location

Related Publications (1)

• 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.

  PMID: 27539372 RESULT

MeSH Terms

Interventions

Warfarin; Fluconazole; Rifampin

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Triazoles; Azoles; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Richard Brundage
• Organization: University of Minnesota

brund001@umn.edu

612-624-3115

Study Officials

• Richard Brundage, PhD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2010
• First Posted: October 6, 2011
• Study Start: May 1, 2009
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: November 14, 2018
• Results First Posted: August 18, 2014

Record last verified: 2018-10

Locations

US (1)