An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance

Thromb Haemost. 2016 Aug 1;116(2):337-48. doi: 10.1160/TH15-12-0955. Epub 2016 Apr 28.

Abstract

Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar's two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10(-6)). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10(-6)) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.

Keywords: CYP2C9; CYP4F2; Pharmacogenomics; VKORC1; warfarin.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Anticoagulants / pharmacokinetics*
  • Atrial Fibrillation / blood
  • Atrial Fibrillation / drug therapy
  • Atrial Fibrillation / genetics
  • Cohort Studies
  • Cytochrome P-450 CYP2C9 / genetics
  • Cytochrome P450 Family 4 / genetics
  • Databases, Factual
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics / statistics & numerical data*
  • Pharmacogenomic Variants
  • Predictive Value of Tests
  • Vitamin K Epoxide Reductases / genetics
  • Warfarin / administration & dosage*
  • Warfarin / adverse effects
  • Warfarin / pharmacokinetics*
  • Young Adult

Substances

  • Anticoagulants
  • Warfarin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases

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