A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9

• Published in: Clinical pharmacology and therapeutics 2006-10, Vol.80 (4), p.346-355
• Main Authors: Tham, Lai‐San, Goh, Boon‐Cher, Nafziger, Anne, Guo, Jia‐Yi, Wang, Ling‐Zhi, Soong, Richie, Lee, Soo‐Chin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Algorithms; Analysis of Variance; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Aryl Hydrocarbon Hydroxylases - genetics; Asian Americans - genetics; Biological and medical sciences; Cohort Studies; Cytochrome P-450 CYP2C9; Female; Haplotypes; Humans; Linear Models; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Reproducibility of Results; Retrospective Studies; Vitamin K Epoxide Reductases; Warfarin - administration & dosage; Warfarin - pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2006.06.009

Introduction Because of the unique lack of genetic diversity despite the multiethnicity in the Asian population, we hypothesize that single‐nucleotide polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9*3) and vitamin K epoxide reductase complex subunit 1 (VKORC1) at position 381, used to infer VKORC1haplotype in combination with demographic factors, can accurately predict warfarin doses. The aims of this study were to derive a pharmacogenetics‐based dosing algorithm by use of retrospective information and to validate it through a data‐splitting method in a separate cohort of equal size. Methods We used 215 records of warfarin patients recruited into a CYP2C9/VKORC1 genotyping study to perform this analysis. Univariate analyses for individual predictors, including age, weight, gender, serum albumin concentration, ethnic group, international normalized ratio, and CYP2C9 and VKORC1 381 genotypes, were conducted to select variables with P < .1 for further inclusion into the multivariate regression analysis. In the final model only predictors reaching a statistical significance of P < .05 were retained. Results Data from 107 subjects undergoing maintenance warfarin therapy with an international normalized ratio stabilized between 2 and 3 were used to derive the final model, as an exponential function of age, weight, CYP2C9*3 allele, and VKORC1 381 CC and TC genotypes, and this model accounted for 60.2% of the variability in daily warfarin dose requirement. The model was validated in a separate cohort of 108 subjects and showed a mean underestimation of 0.23 ± 1.21 mg/d. Conclusion Warfarin dose requirements in Asians can be accurately predicted by use of a combination of patient demographics and a simplified genotyping approach for single variants in CYP2C9 and VKORC1. Clinical Pharmacology & Therapeutics (2006) 80, 346–355; doi: 10.1016/j.clpt.2006.06.009