Pharmacogenetics of Warfarin Induction and Inhibition
Nøkkelord
Abstrakt
Beskrivelse
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.
Datoer
Sist bekreftet: | 09/30/2018 |
Først sendt: | 01/28/2010 |
Anslått påmelding sendt: | 10/03/2011 |
Først lagt ut: | 10/05/2011 |
Siste oppdatering sendt: | 10/14/2018 |
Siste oppdatering lagt ut: | 11/13/2018 |
Dato for første innleverte resultater: | 07/29/2014 |
Dato for første innsendte QC-resultater: | 07/29/2014 |
Dato for første postede resultater: | 08/17/2014 |
Faktisk studiestartdato: | 04/30/2009 |
Anslått primær ferdigstillelsesdato: | 05/31/2013 |
Anslått sluttdato for studien: | 05/31/2013 |
Tilstand eller sykdom
Intervensjon / behandling
Drug: Control - Warfarin only
Drug: Fluconazole - Warfarin
Drug: Rifampin - Warfarin
Fase
Armgrupper
Væpne | Intervensjon / behandling |
---|---|
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. | |
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. | |
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. | |
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. | |
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. |
Kvalifikasjonskriterier
Alder Kvalifisert for studier | 18 Years Til 18 Years |
Kjønn som kan studeres | All |
Godtar sunne frivillige | Ja |
Kriterier | 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. |
Utfall
Primære utfallstiltak
1. Warfarin Clearance. [Over three (two for CYP2C9*1B/*1B participants) 12-16 day study periods.]