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Charles S Eby, Counterpoint: Pharmacogenetic-Based Initial Dosing of Warfarin: Not Ready for Prime Time, Clinical Chemistry, Volume 55, Issue 4, 1 April 2009, Pages 712–714, https://doi.org/10.1373/clinchem.2008.115972
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Availability of the human genome sequence offers the promise of personalized medicine through pharmacogenomics. Warfarin, a member of the coumarin family of oral anticoagulants used to prevent and treat thromboembolic disorders and one of the top 20 prescribed medications in the US, is an ideal drug for applying the principles of pharmacogenetics. Warfarin inhibits reduction of vitamin K epoxide by the vitamin K epoxide reductase complex, subunit 1 (VKORC1)1 enzyme, causing hypogammacarboxylation of vitamin K–dependent coagulation factors and an acquired coagulopathy. Warfarin therapy is monitored with the international normalized ratio (INR) derived from the prothrombin time. The INR therapeutic range is narrow, and the maintenance warfarin dose required to produce a therapeutic INR for an individual is both unpredictable and widely variable, leading to bleeding complications, especially during the initiation period when dose adjustments are made by trial and error(1).
During the past 12 years, discoveries regarding the molecular basis of warfarin pharmacokinetics and pharmacodyanmics have been combined with clinical and demographic information from stably anticoagulated patients to generate many dosing algorithms. Up to 54% of the interpatient variation in therapeutic warfarin dose can be accounted for by the combination of patient age, body size, target INR, and use of amiodaron with the genotypes for 2 single-nucleotide polymorphisms (SNPs) in cytochrome 2C9 that reduce warfarin metabolism and 1 from a group of SNPs in the vitamin K epoxide reductase complex, subunit 1 (VKORC1)2 gene in high linkage disequilibrium and associated with increased sensitivity to warfarin(2). Few pharmacogenetic algorithms have been validated, however, and all are less accurate when used to predict therapeutic warfarin doses in African Americans(3), most likely because of currently unknown genetic mechanisms that affect warfarin sensitivity. Ongoing molecular and translation research has identified additional genetic variants affecting warfarin dosing(4), but to date they are rare or have modest impact on therapeutic dose prediction.
