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A Regulatory Science Perspective on Warfarin Therapy: A Pharmacogenetic Opportunity

From the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.

Warfarin is a challenging drug to accurately dose, both initially and for maintenance, because of its narrow therapeutic range, wide interpatient variability, and long list of factors that can influence dosing. Two million people in the United States are initiated on warfarin therapy annually, and this number is steadily increasing because of the increase in number of eligible patients. Recently, warfarin was reported to be the fourth leading cause of adverse events. The U.S. Food and Drug Administration recognizes that the adverse event rate of warfarin can be improved through better initial dosing, because many of the serious adverse events of warfarin occur soon after starting treatment. A substantial number of studies demonstrate that common variants of two genes, VKORC1 and CYP2C9, along with other nongenetic factors, correlate significantly with warfarin dosing. The genotypes of VKORC1 and CYP2C9 alone account for nearly 3 times more of the variability (30%) in warfarin dosing than do age, weight, gender, and other clinical factors combined (12%). Therefore, the purpose of this report is to review the current recommendations for warfarin therapy that involve genetic testing.

Key Words: Warfarin • pharmacogenetics • CYP2C9 • VKORC1

Address for reprints: Shiew-Mei Huang, PhD, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Rm 3188, Bldg 51, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002; e-mail: shiewmei.huang{at}fda.hhs.gov.

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