Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Abstract

Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, -1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007.

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

“…10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awareness in the clinical community. 16 However, it is important to note that patient demographics, clinical factors, and genetic variants combined explain only 45% to 55% of the total dose variance. 2,3 Both VKORC1 and CYP2C9 were identified to be important as a result of their functional relationship to warfarin pharmacology.…”

Development and Evaluation of a Pharmacogenomics Educational Program for Pharmacists

“…4 In 2007, the FDA changed warfarin labeling to include pharmacogenomics testing considerations, and in 2010, announced the addition of a black-box warning for clopidogrel based on pharmacogenomics metabolism concerns. 5,6 The FDA also has updated the pimozide drug label to include dosing information for CYP2D6 poor metabolizers. 7 These labeling changes are among the first tangible steps toward individualized medication dosing based on a patient's genetic information.…”

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease

“…As a consequence, clotting factors II (prothrombin), Vll, lX, and X do not function normally. Proteins C, S, and Z are affected to a lesser extent 116 ( Figure 6). The gene for the enzyme VKORC1 is on the short arm of chromosome 16.…”

“…It is completely absorbed orally, and 98% to 99% is bound to plasma proteins. 69,116,117 It exists as 2 optically active mirror-image isomers, the R and S enantiomers. The S enantiomer is 2 to 5 times more active than the R enantiomer.…”