CompletedNCT01447511Updated Nov 14, 2018Results posted

Pharmacogenetics of Warfarin Induction and Inhibition

An interventional study of Control - Warfarin only and Fluconazole - Warfarin in Healthy, sponsored by University of Minnesota. Completed at 1 site in United States. Open to participants aged 18 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-11-14.

Sponsored by University of Minnesota · Not applicable, Interventional, and Basic science

Phase: Not applicable
Study type: Interventional
Enrollment: 39
Allocation: Non-randomized
Ages: 18 Years to 60 Years
Sex: All

Study 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.

Read the 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.

Conditions studied

Healthy

Keywords

Drug Interactions
Warfarin
Genetics
CYP2C9
Healthy Volunteers

In context

Lead sponsor

University of Minnesota is the lead sponsor of 1,185 studies on the registry; 196 are open to participants now.

Of its 132 completed or terminated interventional studies of FDA-regulated products, 92 (70%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

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

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 design

Phase: Not applicable
Primary purpose: Basic science
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 39 participants (actual)

Study arms

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 · Drug: Fluconazole - Warfarin · Drug: Rifampin - Warfarin
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 · Drug: Rifampin - Warfarin
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 · Drug: Fluconazole - Warfarin · Drug: Rifampin - Warfarin
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 · Drug: Fluconazole - Warfarin · Drug: Rifampin - Warfarin
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 · Drug: Fluconazole - Warfarin · Drug: Rifampin - Warfarin

Interventions

DrugControl - Warfarin only
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
DrugFluconazole - 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.
Also known as: Diflucan, Coumadin
DrugRifampin - 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.
Also known as: Rifadin, Coumadin

What researchers measure

Primary outcomes

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.
Time frame: Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.

Results

Posted Aug 18, 2014

Participant flow

Control Period

Participant flow — Control Period
Milestone	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype
Started	8	5	9	3	4
Completed	8	5	9	3	4
Not completed	0	0	0	0	0

Fluconazole Period

Participant flow — Fluconazole Period
Milestone	CYP2C91/1 Genotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype
Started	8	9	3	4
Completed	8	8	3	4
Not completed	0	1	0	0

Rifampin Period

Participant flow — Rifampin Period
Milestone	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype
Started	8	5	8	3	4
Completed	8	5	8	2	4
Not completed	0	0	0	1	0

Outcome measures

PrimaryWarfarin 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.

Time frame:: Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.
Reported as:: Mean · mL/h

Warfarin Clearance.
mL/h	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype
S warfarin - Control Period	282 ± 62	246 ± 69	180 ± 49	84 ± 7	71 ± 5
R warfarin - Control Period	136 ± 37	124 ± 54	122 ± 27	95 ± 10	153 ± 38
S warfarin - Fluconazole Period	89 ± 17	NA ± NA	68 ± 22	35 ± 7	36 ± 6
R warfarin - Fluconazole Period	66 ± 13	NA ± NA	68 ± 10	55 ± 13	72 ± 7
S warfarin - Rifampin Period	520 ± 69	486 ± 151	347 ± 140	195 ± 20	157 ± 8
R warfarin - Rifampin Period	342 ± 64	307 ± 151	339 ± 64	368 ± 74	406 ± 108

Statistical analysis

CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = <0.0001
CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = =0.0001
CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = <0.0001
CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = =0.3058
CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = =0.3278
CYP2C9*1/*1 Genotype vs CYP2C9*1B/*1B Haplotype vs CYP2C9*1/*3 Genotype vs CYP2C9*2/*3 Genotype vs CYP2C9*3/*3 Genotype · ANOVA · p = =0.6155

Adverse events

Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
CYP2C91/1 Genotype	—	0/8 (0%)	4/8 (50%)
CYP2C91B/1B Haplotype	—	0/5 (0%)	4/5 (80%)
CYP2C91/3 Genotype	—	0/9 (0%)	6/9 (66.7%)
CYP2C92/3 Genotype	—	0/3 (0%)	0/3 (0%)
CYP2C93/3 Genotype	—	0/4 (0%)	2/4 (50%)

Most frequent other events

Showing 10 of 16

Most frequent other events
Event	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype
FatigueGeneral disorders	0/8	3/5	2/9	0/3	0/4
Common Cold SymptomsGeneral disorders	0/8	0/5	4/9	0/3	1/4
HeadacheNervous system disorders	0/8	2/5	4/9	0/3	1/4
Stomach PainGastrointestinal disorders	1/8	2/5	0/9	0/3	0/4
DizzinessNervous system disorders	2/8	0/5	2/9	0/3	1/4
Skin AbrasionSkin and subcutaneous tissue disorders	0/8	0/5	0/9	0/3	1/4
VomitingGastrointestinal disorders	2/8	0/5	0/9	0/3	0/4
NauseaGastrointestinal disorders	1/8	0/5	2/9	0/3	0/4
RashSkin and subcutaneous tissue disorders	0/8	0/5	2/9	0/3	0/4
BruisingInjury, poisoning and procedural complications	0/8	1/5	1/9	0/3	0/4

Baseline characteristics

Age, Continuous
Age, Continuous(years)	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype	Total
Median	22 (19 to 54)	23 (22 to 31)	26 (18 to 52)	28 (21 to 51)	29 (19 to 33)	25 (18 to 54)

Age, Categorical
Age, Categorical(Participants)	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype	Total
<=18 years	0	0	1	0	0	1
Between 18 and 65 years	8	5	8	3	4	28
>=65 years	0	0	0	0	0	0

Sex: Female, Male
Sex: Female, Male(Participants)	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype	Total
Female	4	2	5	3	0	14
Male	4	3	4	0	4	15

Region of Enrollment
Region of Enrollment(participants)	CYP2C91/1 Genotype	CYP2C91B/1B Haplotype	CYP2C91/3 Genotype	CYP2C92/3 Genotype	CYP2C93/3 Genotype	Total
United States	8	5	9	3	4	29

Study locations

1 site

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

References and documents

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. PubMed 27539372 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Nov 14, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01447511
Lead sponsor: University of Minnesota
Collaborators: National Institute of General Medical Sciences (NIGMS)
Responsible party: Sponsor
First posted: Oct 6, 2011
Start date: May 2009
Primary completion: Jun 2013
Completion: Jun 2013
Results posted: Aug 18, 2014
Last update: Nov 14, 2018

Study contacts

Richard Brundage, PhD

principal investigator · University of Minnesota

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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