Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing

Abstract

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.(1).

Figure 1

Schematic representation of warfarin metabolism and its mechanism of action. Warfarin is administered via a racemic mixture of the R- and S- stereoisomers. S-warfarin is three to five times more potent than R-warfarin and is metabolized predominantly to 7- and 6-hydroxyl metabolites via CYP2C9. Warfarin exerts its anticoagulant effect through inhibition of its molecular target, VKORC1, which in turn limits availability of reduced vitamin K, leading to decreased formation of functionally active clotting factors. these clotting factors are glycoproteins that are postranslationally carboxylated by γ-glutamyl carboxylase (GGCX) to Gla-containing proteins. the endoplasmic reticulum chaperone protein calumenin (CALU) can bind to and inhibit GGCX activity. the metabolism of reduced vitamin K to hydroxyvitamin K1 is catalyzed by CYP4F2, which removes vitamin K from the vitamin K cycle. Adapted from the warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways provided at PharmGKB, <http://www.pharmgkb.org/do/serve?objId=PA451906&objcls=Drug#tabview=tab4>.

Figure 2

Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 −1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1*1 for US Food and Drug Administration (FDA) table and algorithm dosing). the range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. the range of doses predicted using the IWPc dosing algorithm in these 3,616 patients is shown by the solid lines.