Pharmacogenetics of Warfarin Induction and Inhibition
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| ClinicalTrials.gov Identifier: NCT01447511 |
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Recruitment Status :
Completed
First Posted : October 6, 2011
Results First Posted : August 18, 2014
Last Update Posted : November 14, 2018
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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 or disease | Intervention/treatment | Phase |
|---|---|---|
| Healthy | Drug: Control - Warfarin only Drug: Fluconazole - Warfarin Drug: Rifampin - Warfarin | Not Applicable |
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 (Clinical Trial) |
| Actual Enrollment : | 39 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Basic Science |
| Official Title: | Pharmacogenetics of Warfarin Induction and Inhibition |
| Study Start Date : | May 2009 |
| Actual Primary Completion Date : | June 2013 |
| Actual Study Completion Date : | June 2013 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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:
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:
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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.
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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:
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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.
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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:
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:
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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.
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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:
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:
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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.
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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:
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:
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- Warfarin Clearance. [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
| Sexes Eligible for Study: | 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:
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01447511
| United States, Minnesota | |
| Clinical and Translational Science Institute | |
| Minneapolis, Minnesota, United States, 55414 | |
| Principal Investigator: | Richard Brundage, PhD | University of Minnesota |
| Responsible Party: | University of Minnesota |
| ClinicalTrials.gov Identifier: | NCT01447511 |
| Other Study ID Numbers: |
0807M38361 P01GM032165-26 ( U.S. NIH Grant/Contract ) |
| First Posted: | October 6, 2011 Key Record Dates |
| Results First Posted: | August 18, 2014 |
| Last Update Posted: | November 14, 2018 |
| Last Verified: | October 2018 |
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Drug Interactions Warfarin Genetics CYP2C9 Healthy Volunteers |
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Rifampin Fluconazole Warfarin Anticoagulants Antibiotics, Antitubercular Antitubercular Agents Anti-Bacterial Agents Anti-Infective Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers |
Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP3A Inducers Antifungal Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP2C19 Inhibitors |