Pharmacogenetics of warfarin: development of a dosing algorithm for brazilian patients

Clin Pharmacol Ther. 2008 Dec;84(6):722-8. doi: 10.1038/clpt.2008.166. Epub 2008 Aug 27.

Abstract

A dosing algorithm including genetic (VKORC1 and CYP2C9 genotypes) and nongenetic factors (age, weight, therapeutic indication, and cotreatment with amiodarone or simvastatin) explained 51% of the variance in stable weekly warfarin doses in 390 patients attending an anticoagulant clinic in a Brazilian public hospital. The VKORC1 3673G>A genotype was the most important predictor of warfarin dose, with a partial R(2) value of 23.9%. Replacing the VKORC1 3673G>A genotype with VKORC1 diplotype did not increase the algorithm's predictive power. We suggest that three other single-nucleotide polymorphisms (SNPs) (5808T>G, 6853G>C, and 9041G>A) that are in strong linkage disequilibrium (LD) with 3673G>A would be equally good predictors of the warfarin dose requirement. The algorithm's predictive power was similar across the self-identified "race/color" subsets. "Race/color" was not associated with stable warfarin dose in the multiple regression model, although the required warfarin dose was significantly lower (P = 0.006) in white (29 +/- 13 mg/week, n = 196) than in black patients (35 +/- 15 mg/week, n = 76).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms*
  • Ambulatory Care
  • Amiodarone / administration & dosage
  • Amiodarone / pharmacokinetics
  • Analysis of Variance
  • Aryl Hydrocarbon Hydroxylases / drug effects
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Brazil
  • Cohort Studies
  • Cytochrome P-450 CYP2C9
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Ethnicity / genetics
  • Female
  • Genotype
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / drug effects
  • Mixed Function Oxygenases / genetics*
  • Multivariate Analysis
  • Pharmacogenetics*
  • Polymorphism, Genetic*
  • Retrospective Studies
  • Risk Assessment
  • Sensitivity and Specificity
  • Simvastatin / administration & dosage
  • Simvastatin / pharmacokinetics
  • Treatment Outcome
  • Vitamin K Epoxide Reductases
  • Warfarin / administration & dosage
  • Warfarin / pharmacokinetics*
  • Young Adult

Substances

  • Warfarin
  • Simvastatin
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • Amiodarone