Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin

Abstract

Objective: Our objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. Methods: Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R‐ and S‐warfarin, and triglyceride concentrations. Results: A total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild‐type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 ± 1.72 mg in homozygous wild‐type patients to 3.63 ± 1.78 mg for *1/*2‐positive patients and 2.70 ± 1.36 mg for *1/*3‐positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P < .001), genotype (r = 0.24, P < .005), and age and genotype together (r = 0.45, P < .005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P = .02), body weight (r = 0.25, P = .005), and plasma vitamin K concentration (r = 0.18, P < .05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S‐warfarin clearance (r = 0.34, P < .0001) but none on R‐warfarin clearance. Conclusion: This study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long‐term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy. Clinical Pharmacology & Therapeutics (2004) 75, 204–212; doi: 10.1016/j.clpt.2003.10.001