Warfarin Therapy and and Genotype

Warfarin (brand name Coumadin) is an anticoagulant (blood thinner). Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors and is used in the prevention and treatment of various thrombotic disorders. Warfarin is a drug with narrow therapeutic index; thus, a small change in its plasma levels may result in concentration dependent adverse drug reactions or therapeutic failure. Therefore, the dose of warfarin must be tailored for each patient according to the patient’s response, measured as INR (International Normalized Ratio), and the condition being treated. There is a wide inter-individual variability in the dose of warfarin required to achieve target anticoagulation, and the time it takes to reach target INR. Approximately half of this variability is known to be caused by clinical or lifestyle factors (e.g., a patient’s age, weight, BMI, gender, smoking status, existing conditions, and concomitant medications) and by genetic factors (known genetic factors include variants in the , , genes, and the rs12777823 variant in the gene cluster on chromosome 10) (1). The and genotypes are the most important known genetic determinants of warfarin dosing. Warfarin targets VKORC1, an enzyme involved in vitamin K recycling. A common variant, , c.-1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. The CYP2C9 enzyme metabolizes warfarin and the variants and , are also associated with lower dose requirements. The FDA-approved drug label for warfarin states that and genotype information, when available, can assist in the selection of the initial dose of warfarin. The label provides 2 sets of warfarin dosing recommendations, for when the and genotypes are either known (Table 1) or not known (taking into account clinical factors, the initial dose of warfarin is usually 2–5 mg once daily) (1). In addition, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) has published recommendations for the initial standard dose of warfarin. A dose reduction is recommended for individuals who are CYP2C9 poor and intermediate metabolizers (with the exception of intermediate metabolizers with the CYP2C9*1/*2 genotype, no dose change is required), and a dose reduction is recommended for individuals who carry 2 copies of the variant A allele c.-1639G>A/A (Table 2) (2, 3). Recently, genetic variation in the gene, and a variant near the gene cluster, rs12777823, have been associated with influencing warfarin therapy. The variant is associated with a modest increase in warfarin dose requirements in individuals with European or Asian ancestry, while in individuals with African ancestry, the rs12777823 A/G or A/A genotype is associated with decreased warfarin dose requirements. The 2017 Update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing, provides warfarin dosing recommendations for adults with and without African ancestry, and also for pediatric patients (see Therapeutic Recommendations). CPIC recommends that these dosing guidelines are applied after a warfarin dose has been calculated using a validated pharmacogenetic algorithm, which includes genotype information for c.-1639G>A and and (Figure 1) (4)