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Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

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Abstract

Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007.

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Authors and Affiliations

  1. Washington University Medical Center, 660 S. Euclid Ave, Campus Box 8005, St. Louis, MO, 63110, USA

    Brian F. Gage

  2. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, USA

    Lawrence J. Lesko

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  1. Brian F. Gage
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  2. Lawrence J. Lesko
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Correspondence to Brian F. Gage.

Additional information

Disclosure: A portion of this article was adapted from an education handout that Dr. Gage has retained copyright of: Gage, B.F. (2006). Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program: 467–473. Dr. Gage has served as a consultant to Bristol-Myers Squibb.

Funding: NIH R01 HL074724.

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Gage, B.F., Lesko, L.J. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 25, 45–51 (2008). https://doi.org/10.1007/s11239-007-0104-y

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