Warfarin Sensitivity

Warfarin Sensitivity

 

Warfarin (Coumadin®) is one of the most widely used anticoagulants worldwide, with potentially severe hemorrhagic consequences if it is dosed incorrectly.  The labeling for Coumadin® was revised in August, 2007 to include information about how pharmacogenetic variants affect dose requirements (NDA 9-218/S-105).

Genetic Risk Factors for Hypercoagulation

  • CYP2C9 variants affect warfarin clearance
    • *2 allele (430C>T)
      • Reduces metabolism of s-warfarin by approximately 30%
      • Extends half-life, requiring a longer time to achieve steady state
      • Average daily warfarin requirement is approximately 17% lower in patients with one copy of CYP2C9*2, as compared to a patient with no CYP2C9 variants
      • Allele frequency of the CYP2C9*2 allele in Caucasians is approximately 11%
    • *3 allele (1075A>C)
      • Reduces metabolism of s-warfarin by approximately 80%
      • Extends half-life of the drug, requiring a longer time to achieve steady state
      • Average daily warfarin requirement is approximately 37% lower in patients with one copy of CYP2C9*3, as compared to a patient with no CYP2C9 variants
      • Allele frequency of the CYP2C9*2 allele in Caucasians is approximately 7%
  • VKORC1 variants affect response to warfarin
    • Many variants are known and exist in linkage disequilibrium
    • Genotyping to detect a common promoter variant (-1639G>A) predicts warfarin sensitivity  
    • Average daily warfarin requirement is approximately 20% lower in patients with one copy of the promoter variant, as compared to a patient with no VKORC1 variants
    • Allele frequency of the -1639G>A variant in Caucasians is approximately 40%
  • Combinations of variants from one or more genes will reduce the average daily warfarin requirement further

Pathophysiology

  • Warfarin is prescribed for
    • Atrial fibrillation
    • Venous thromboembolism
    • Mechanical heart valves
    • Postoperative prophylaxis
  • Warfarin inhibits production of vitamin K-dependent coagulation factors through inhibition of vitamin K epoxide reductase (VKOR)
  • Warfarin is metabolized in the liver by the cytochrome P450 enzymes
    • S-warfarin, the more potent of the two enantiomers, is metabolized primarily by CYP2C9
    • A variety of drugs and illnesses can affect the metabolism of warfarin
  • Pharmacogenetics affect dosing
    • CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing
    • VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing
    • Combining genotypes with clinical factors may account for up to 79% of variability in warfarin dosing.

Diagnosis

  • CYP2C9 genotyping
  • VKORC1 genotyping

Treatment

  • Genotype-based dosing of warfarin
    • Many algorithms and models for dosing are published
    • Algorithms predict maintenance dose but do not necessarily predict pharmacokinetic differences that may influence the time required to achieve steady state, and therefore, do not provide guidance on dosing intervals or when interpretation of an INR result is appropriate
  • On-line dosing algorithm example: Click here for Warfarindosing.org
  • Dosing equation example from Sconce 2005
    • Square root of the dose (mg/d) = 0.628 – 0.0135 (age in years) – 0.240 (a) – 0.370 (b) – 0.241 (c) + 0.0162 (height in cm)
      • a = CYP2C9*2, input 0, 1, 2 based on number of alleles
      • b = CYP2C9*3, input 0, 1, 2 based on number of alleles
      • c = VKORC1, input 1 for GG, 2 for GA, 3 for AA
  • When dosing, consider warfarin drug interactions  Click here for a complete list of drugs that are metabolized by a specific cytochrome P450 isoform
  • Pharmacogenetic testing does not replace the need to monitor warfarin therapy through Prothrombin Time/International Normalized Ratio (INR) testing