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The Impact of PGx on Warfarin Dosing

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Vol. 17 • Issue 11 • Page 20
The Molecular Edge

Pharmacogenetics (PGx) refers to the study of individual genes, especially the ones that encode drug-metabolizing enzymes, as they relate to drug effects. Pharmacogenomics refers to the study of multiple genetic factors as they simultaneously relate to drug effects. Essentially, pharmacogenetic is to pharmacogenomic as gene is to genome; nonetheless, the terms are often used loosely and interchangeably.

Concepts of Polymorphisms

With regard to pharmacogenomics, it is useful to recall the concepts of polymorphism. Polymorphisms are variations in genes (sequences other than the wild-type) that exist stably in the population (present in >1 percent of the population) and generally are benign (i.e., are not disease-causing). Single nucleotide polymorphisms (SNPs) are the most common type of polymorphism. In specific circumstances, polymorphisms may be beneficial (e.g., some benign red blood cell polymorphisms are protective against malaria). Alternatively, polymorphisms can be pathologic (e.g., many polymorphisms have no clinical effects unless the individual is exposed to a toxin or drug). For instance, it has long been recognized that certain individuals become ill upon ingestion of fava beans. This phenomenon, favism, highlights another recurring feature in pharmacogenomics: the frequency of a particular polymorphism often varies significantly from one population group to another. Favism, for instance, is found particularly in Middle Eastern populations.

Optimizing Drug Therapy

Personalized medicine is becoming an increasingly popular method to optimize drug therapy based on genetic variation. The paradigm shift in the clinical management of patients is visible in routine patient care to oncology services. Pharmacogenetics is now supported by the FDA, which in 2006 began its "Critical Path to Personalized Medicine" program as an initiative to individualize drug dosage and improve the safety and efficacy of drug therapy (www.fda.gov/oc/initiative/criticalpath/warfarin.html). Because of its narrow therapeutic range, widespread use and high risk for adverse drug reactions, warfarin (Coumadin), used to treat individuals with tendencies to clot, is an exemplary model of the clinical applications of pharmacogenetics.

More than 7 percent of patients undergoing warfarin therapy experience major or fatal bleeding events. The most commonly used anticoagulant in the world, warfarin is a second most common drug associated with emergency room visits in the U.S. (www.fda.gov/cder/drug/inforpage/wardin/qa.htm). The high probability of adverse reactions makes physicians reluctant to prescribe warfarin, and the drug is therefore potentially underutilized for the prophylaxis of thromboembolic stroke. The risk of bleeding or thromboembolism is highest during the induction period. Because warfarin dosing requirements vary substantially among individuals due to genetic variation, in August 2007 the FDA mandated new labeling on Coumadin. The new labeling provided information about allelic variants known to affect the warfarin maintenance dose and encourages physicians to utilize patient genotypes for individualized warfarin therapy. This dosing technique also has been the subject of several clinical studies in patients being treated with the generic anticoagulant warfarin.

Individual variation in drug metabolism can be attributed to polymorphisms present in a large group of enzymes (and responsible genes) that comprise the cytochrome P450 system, whose purpose is the oxidative metabolism of toxins (including medications). The liver is the major source of cytochrome P450 enzymes, with greater than 25 known subtypes showing hepatic expression. Other organs, such as the brain and intestines, show alternate expression patterns. Genetic variations in the cytochrome P450 genes may lead to enhanced, reduced or absent activity.

Terminology

The terminology to describe individual cytochrome P450 enzymes and their variants is somewhat complex, but in general it is relatively easy to decipher (Table). Although confusing initially, genetic nomenclature allows for the standardization of genotypic information.

Effects on Warfarin

CYP2C9 is responsible for the breakdown and metabolism of warfarin in the body. Several CYP2C9 polymorphisms have been associated with reduced CYP2C9 activity (thus reduced warfarin metabolism) and a two- to threefold elevated risk of an adverse event when beginning warfarin.1Two of these polymorphisms are fairly common-CYP2C9*2 and CYP2C9*3-each present in approximately 10 percent of the Caucasian population. The incidence is considerably lower in African-American, Hispanic and Asian groups. Other SNPs (CYP2C9*5, for example) have shown to be more prevalent in African-American populations when compared to other ethnic groups.

Warfarin acts through the inhibition of VKORC1 (vitamin K epoxide reductase), which is involved in maintaining high levels of vitamin K necessary for the functioning of some coagulation factors. Warfarin response is also modulated by VKORC1 gene polymorphisms.2Several variant alleles referred to as H1, H2, etc. impact warfarin metabolism. For example, H1 and H2 (VKORC1 1173C>T SNP) have been associated with enhanced sensitivity to warfarin (requiring lower doses), while H7, H8 and H9 haplotypes (VKORC1 3730G>A SNP) have been associated with relative warfarin resistance (requiring higher doses).

Improved Strategies

Data pinpoint CYP2C9 and VKORC1 as the source of a significant proportion of the variation observed in warfarin dose among individuals. Consequently, laboratory testing for common genetic variations in CYP2C9 and VKORC1 has become standard in many clinical molecular laboratories. Such pharmacogenetic information, coupled with improved clinical algorithms, is providing new and improved strategies for reducing the risks of therapeutic overdosing or under-dosing high-risk patients when initiating warfarin therapy.3

Dr. Nordberg is associate professor, Departments of Pathology and Pediatrics; director, Molecular Pathology, Feist-Weiller CancerCenter, Louisiana State University Health Sciences Center, Shreveport; and chair of the Genetics Subdivision for the Association of Molecular Pathology.

References

1. Adcock DM, C. Koftan, D Crisan, et al. Effect of polymorphisms in the cytochrome P450 CYP2C9 gene on warfarin anticoagulation. Arch Pathol Lab Med 2004; 128:1360-1363.

2. Rieder MJ, AP Reiner, BF Gage et al. Effect of VKORC1 haplotypes on trascriptional regulation and warfarin dose. N Engl J Med 2005; 352(2):2285-2293.

3. Gage, BF, C Eby, JA Johnson et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008;84(3):326-31.

Table

CYP2C9*1*2 can be defined as:

CYP = species (P450 is used for all mammalian species)

2 = family (14 to 17 in humans)

C = subfamily (42 in humans)

9 = enzyme/gene (55 genes, 29 pseudogenes in humans)

*1 *2 = alleles or variants with *1 being the wild-type




     

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