Genotyping to Optimize Individualized Drug Therapy

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Interindividual variability in drug responsiveness is marked and related to between subject differences in the drug's disposition/pharmacokinetics and/or pharmacodynamics. In turn, variability in drug disposition, generally, reflects the interplay between environmental and genetic factors. With the rapid advances in knowledge about the human genome and recognition that variability at the DNA level is common, an exciting notion of potentially major clinical importance postulates that genetic information about an individual will ultimately allow drug therapy to be "tailored" to that particular patient. Appropriate technology to routinely provide information on single nucleotide polymorphisms (SNPs) and other genetic variability will, undoubtedly, become more available in the near future. However, the validity and potential benefits of a pharmacogenetic strategy, involving pre-prescription genotyping, for the routine therapeutic management of patients has yet to be tested and proven. This Project proposes to investigate this question through the use of warfarin as an index probe of a drug with a narrow therapeutic index and large differences in its metabolism associated with allelic variants of cytochrome P4502C9 (CYP2C9). In Specific Aim 1, studies are proposed in healthy subjects to determine the functional consequences on warfarin?s metabolism of a newly discovered variant CYP2C9*5 that is selectively expressed in African-Americans. By contrast, Specific Aim 2 focuses on the consequences of genetic variability in CYP2C9 associated with the *1, *2, *3 and *5 alleles in European- and African-American patients receiving anticoagulant therapy with warfarin. This observational study will indicate the relationship between a specific CYP2C9 genotype and the optimal warfarin dose in such patients. Subsequently, such information will be used in a prospective, randomized study in Specific Aim 3 to test the hypothesis that initiating warfarin therapy based on an individual patient?s genotype will improve clinical outcome compared to the current standard-care approach based on empirical optimization of the dose.