Warfarin Sensitivity

Clinical Background

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 mutations affect dose requirements (NDA 9-218/S-105).

Epidemiology

Incidence of CYP2C9*2 – Caucasians 0.08-0.13, Asians 0.02-0.06, African Americans less than 0.01.
Incidence of CYP2C9*3 – Caucasians 0.06-0.10, Asians less than 0.01, African Americans 0.01-0.04

Risk Factors

CYP2C9 mutations 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 mutations
  - 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 mutations
  - Allele frequency of the CYP2C9*2 allele in Caucasians is approximately 7%
VKORC1 mutations affect response to warfarin
- Many mutations are known and exist in linkage disequilibrium
- Genotyping to detect a common promoter mutation (-1639G>A) predicts warfarin sensitivity
- Average daily warfarin requirement is approximately 20% lower in patients with one copy of the promoter mutation, as compared to a patient with no VKORC1 mutations
- Allele frequency of the -1639G>A mutation in Caucasians is approximately 40%
Combinations of mutations 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

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
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Test Name and Number	Recommended Use	Limitations	Follow Up
Warfarin Sensitivity (CYP2C9 & VKORC1 ) 3 Mutations 0051370 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Confirm presence of genotypes that affect metabolism of and response to warfarin Only the two common CYP2C9 and one common VKORC1 mutations will be detected Clinical sensitivity: 90% of CYP2C9 and VKORC1 mutations causing warfarin sensitivity in Caucasians are detected; the detection rate in other ethnicities is reduced	Other mutations that may impact warfarin sensitivity or resistance in these genes or other genes will not be detected Rare mutations within primer or probe regions may interfere with the assay	Counseling and informed consent are recommended for genetic testing
Cytochrome P450 2C9 (CYP2C9) 2 Mutations 0051103 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Confirm presence of genotypes that affect metabolism of warfarin Only the two common CYP2C9 mutations will be detected Clinical sensitivity: 90% of deleterious CYP2C9 mutations are detected in Caucasians; sensitivity is not well characterized in other ethnicities	Additional mutations in this or other genes will not be detected Mutation detection is not a substitute for therapeutic drug or other clinical monitoring Non-genetic factors may also affect drug metabolism

Test Name and Number

Recommended Use

Limitations

Follow Up

Warfarin Sensitivity (CYP2C9 & VKORC1 ) 3 Mutations 0051370

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm presence of genotypes that affect metabolism of and response to warfarin

Only the two common CYP2C9 and one common VKORC1 mutations will be detected

Clinical sensitivity: 90% of CYP2C9 and VKORC1 mutations causing warfarin sensitivity in Caucasians are detected; the detection rate in other ethnicities is reduced

Other mutations that may impact warfarin sensitivity or resistance in these genes or other genes will not be detected

Rare mutations within primer or probe regions may interfere with the assay

Counseling and informed consent are recommended for genetic testing

Cytochrome P450 2C9 (CYP2C9) 2 Mutations 0051103

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm presence of genotypes that affect metabolism of warfarin

Only the two common CYP2C9 mutations will be detected

Clinical sensitivity: 90% of deleterious CYP2C9 mutations are detected in Caucasians; sensitivity is not well characterized in other ethnicities

Additional mutations in this or other genes will not be detected

Mutation detection is not a substitute for therapeutic drug or other clinical monitoring

Non-genetic factors may also affect drug metabolism

Additional Tests Available

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Test Name and Number	Comments
Warfarin, Urine 0091230 Method: High Performance Liquid Chromatography
Warfarin, Serum or Plasma 0090805 Method: High Performance Liquid Chromatography