Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update

Abstract

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

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 3-5 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 post-translationally carboxylated by gamma-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 warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways at PharmGKB, http://www.pharmgkb.org/do/serve?objId=PA451906&objCls=Drug#tabview=tab4).

Figure 2. Dosing recommendations for Warfarin dosing based on genotype for adult patients

^a“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach ^bData strongest for European and East Asian ancestry populations and consistent in other populations. ^c45-50% of individuals with self-reported African ancestry carry CYP2C9*5,*6,*8,*11, or rs12777823. IF CYP2C9*5, *6, *8, and *11 WERE NOT TESTED, DOSE WARFARIN CLINICALLY. Note: these data derive primarily from African Americans, who are largely from West Africa. It is unknown if the same associations are present for those from other parts of Africa. ^dMost algorithms are developed for the target INR 2-3. ^eConsider an alternative agent in individuals with genotypes associated with CYP2C9 poor metabolism (e.g., CYP2C9*3/*3, *2/*3, *3/*3) or both increased sensitivity (VKORC1 A/G or A/A) and CYP2C9 poor metabolism. ^fSee the EU-PACT trial for pharmacogenetics-based warfarin initiation (loading) dose algorithm (33) with the caveat that the loading dose PG algorithm has not been specifically tested or validated in populations of African ancestry. ^gLarger dose reduction might be needed in variant homozygotes (i.e. 20-40%). ^hAfrican American refers to individuals mainly originating from West Africa.

Figure 3. Dosing recommendations for Warfarin dosing based on genotype for pediatric patients

^aData strongest for European ancestry populations and consistent in most Japanese studies. ^b“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach ^cValidated published pediatric pharmacogenetic algorithms include Hamberg et al.(42) and Biss et al.(41) ^dNo studies in children included CYP2C9*5, *6, *8, or *11 genotyping.