Healthy
Conditions
Keywords
Drug Interactions, Warfarin, Genetics, CYP2C9, Healthy Volunteers
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.
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.
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.
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.
Sponsors
National Institute of General Medical Sciences (NIGMS)
University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Warfarin Clearance. | 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. |
Countries
United States
Participant flow
Pre-assignment details
Thirty-nine participants were enrolled in the study; however, only twenty-nine of the enrolled participants participated in the study. Per study protocol, participants with the CYP2C9\*1B/\*1B haplotype did not complete the Fluconazole Period. Individuals with the CYP2C9\*1B/\*1B haplotype only completed the Control Period and Rifampin Period.
Participants by arm
| Arm | Count |
|---|---|
| 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 periods: Control Period, Fluconazole Period, and Rifampin Period. | 8 |
| CYP2C9*1B/*1B Haplotype Individuals with the CYP2C9\*1B/\*1B haplotype have two \*1B alleles and participated in the following periods: Control Period and Rifampin Period. | 5 |
| CYP2C9*1/*3 Genotype Individuals with the CYP2C9\*1/\*3 genotype have one \*1 allele and one \*3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. | 9 |
| CYP2C9*2/*3 Genotype Individuals with the CYP2C9\*2/\*3 genotype have one \*2 allele and one \*3 allele and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. | 3 |
| CYP2C9*3/*3 Genotype Individuals with the CYP2C9\*3/\*3 genotype have two \*3 alleles and participated in the following periods: Control Period, Fluconazole Period, and Rifampin Period. | 4 |
| Total | 29 |
Baseline characteristics
| Characteristic | CYP2C9*1/*1 Genotype | CYP2C9*1B/*1B Haplotype | CYP2C9*1/*3 Genotype | CYP2C9*2/*3 Genotype | CYP2C9*3/*3 Genotype | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 5 Participants | 8 Participants | 3 Participants | 4 Participants | 28 Participants |
| Age, Continuous | 22 years | 23 years | 26 years | 28 years | 29 years | 25 years |
| Region of Enrollment United States | 8 participants | 5 participants | 9 participants | 3 participants | 4 participants | 29 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 5 Participants | 3 Participants | 0 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 4 Participants | 0 Participants | 4 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 4 / 5 | 6 / 9 | 0 / 3 | 2 / 4 |
| serious Total, serious adverse events | 0 / 8 | 0 / 5 | 0 / 9 | 0 / 3 | 0 / 4 |
Outcome results
Primary
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.
Population: Participants with the CYP2C9\*1B/\*1B haplotype did not participate in the fluconazole period (inhibition). One CYP2C9\*1/\*3 participant only completed the control period. One CYP2C9\*2/\*3 participant only completed the control and fluconazole (inhibition) study periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | S warfarin - Control Period | 282 mL/h | Standard Deviation 62 |
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | S warfarin - Fluconazole Period | 89 mL/h | Standard Deviation 17 |
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | R warfarin - Rifampin Period | 342 mL/h | Standard Deviation 64 |
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | S warfarin - Rifampin Period | 520 mL/h | Standard Deviation 69 |
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | R warfarin - Fluconazole Period | 66 mL/h | Standard Deviation 13 |
| CYP2C9*1/*1 Genotype | Warfarin Clearance. | R warfarin - Control Period | 136 mL/h | Standard Deviation 37 |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | S warfarin - Control Period | 246 mL/h | Standard Deviation 69 |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | R warfarin - Control Period | 124 mL/h | Standard Deviation 54 |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | S warfarin - Fluconazole Period | NA mL/h | — |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | R warfarin - Fluconazole Period | NA mL/h | — |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | S warfarin - Rifampin Period | 486 mL/h | Standard Deviation 151 |
| CYP2C9*1B/*1B Haplotype | Warfarin Clearance. | R warfarin - Rifampin Period | 307 mL/h | Standard Deviation 151 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | R warfarin - Control Period | 122 mL/h | Standard Deviation 27 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | S warfarin - Rifampin Period | 347 mL/h | Standard Deviation 140 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | S warfarin - Control Period | 180 mL/h | Standard Deviation 49 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | S warfarin - Fluconazole Period | 68 mL/h | Standard Deviation 22 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | R warfarin - Rifampin Period | 339 mL/h | Standard Deviation 64 |
| CYP2C9*1/*3 Genotype | Warfarin Clearance. | R warfarin - Fluconazole Period | 68 mL/h | Standard Deviation 10 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | R warfarin - Rifampin Period | 368 mL/h | Standard Deviation 74 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | S warfarin - Fluconazole Period | 35 mL/h | Standard Deviation 7 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | R warfarin - Fluconazole Period | 55 mL/h | Standard Deviation 13 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | S warfarin - Control Period | 84 mL/h | Standard Deviation 7 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | S warfarin - Rifampin Period | 195 mL/h | Standard Deviation 20 |
| CYP2C9*2/*3 Genotype | Warfarin Clearance. | R warfarin - Control Period | 95 mL/h | Standard Deviation 10 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | S warfarin - Rifampin Period | 157 mL/h | Standard Deviation 8 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | S warfarin - Control Period | 71 mL/h | Standard Deviation 5 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | R warfarin - Rifampin Period | 406 mL/h | Standard Deviation 108 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | R warfarin - Control Period | 153 mL/h | Standard Deviation 38 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | R warfarin - Fluconazole Period | 72 mL/h | Standard Deviation 7 |
| CYP2C9*3/*3 Genotype | Warfarin Clearance. | S warfarin - Fluconazole Period | 36 mL/h | Standard Deviation 6 |
Comparison: The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under control conditions is the same.p-value: <0.0001ANOVA
Comparison: The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under fluconazole conditions is the same.p-value: =0.0001ANOVA
Comparison: The null hypothesis is that the mean S-warfarin clearance among the five CYP2C9 genotypes under rifampin conditions is the same.p-value: <0.0001ANOVA
Comparison: The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under control conditions is the same.p-value: =0.3058ANOVA
Comparison: The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under fluconazole conditions is the same.p-value: =0.3278ANOVA
Comparison: The null hypothesis is that the mean R-warfarin clearance among the five CYP2C9 genotypes under rifampin conditions is the same.p-value: =0.6155ANOVA