M. J. Kim, S. M. Huang, F. W. Frueh, A. N. Rahman, Y. M. Choi, K. M. Robie Suh, G. Shashaty, R. Rieves, L. J. Lesko, CDER, FDA, Silver Spring, MD
The use of pharmacogenomic (PG) information to support the dosing, safety and efficacy of drugs is emerging. Warfarin, an anticoagulant with a narrow therapeutic range, is indicated for the prevention and/or treatment of thromboembolic events. The major adverse event associated with warfarin is bleeding. The S-enantiomer (the pharmacologically most active form) of warfarin is metabolized to 7-hydroxywarfarin by CYP2C9. The frequencies of the CYP2C9*2 and 3 alleles are approximately 11% and 7%, respectively, in Caucasians. CYP2C9*2 and *3 variant alleles decrease CYP2C9 enzymatic activity by 30% and 80%, respectively. Patients with these variant alleles have lower clearance of S-warfarin compared to patients with the wild type (*1/*1) resulting in a lower daily warfarin dose requirement to achieve a given INR. In addition, these patients require a longer duration to achieve stable dosing and have an increased risk of a serious bleeding event (HR, 2.39; 95% CI, 1.18-4.86). VKORC1 has an independent effect on warfarin dose requirements and patients with certain genetic variations in the VKORC1 gene require lower warfarin doses to achieve adequate anticoagulation. Combining information from CYP2C9 and VKORC1 genotyping along with additional factors, such as age and body weight, explain up to 56% of the variability in warfarin dose requirements between patients. Thus, PG testing has the potential to better inform individual dosing decisions regarding warfarin and improve the benefit/risk ratio. Current evidence related to the influence of PG on warfarin dosing was presented at the Clinical Pharmacology Subcommittee of the Advisory Committee (AC) for Pharmaceutical Science in November 2005 (http://www.fda.gov/ohrms/dockets/ac/cder05.html#PharmScience). The AC recommends that PG information be considered to better inform prescribers about risk factors for overanticoagulation.