Warfarin dose adjustments based on CYP2C9 genetic polymorphisms

The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing.

Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles.

Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.