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Warfarin dose influenced by both CYP2C9 and VKORC1
Compared with cytochrome P-450 2C9 (CYP2C9), genetic variability in the pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), was more strongly linked with initial variability in the international normalized ratio response to the drug.
To determine the role of VKORC1 during initial anticoagulation with warfarin, researchers from Vanderbilt University in Nashville, Tenn., analyzed the CYP2C9 genotypes and VKORC1 haplotypes in 297 patients starting warfarin therapy. The researchers also used the international normalized ratio to assess patients’ response to treatment.
Patients with A/A haplotype of VKORC1 had shorter time to the first INR within the therapeutic range (P=.02) and the first INR of more than four (P=.003), compared with patients with non-A/non-A haplotype. CYP2C9, however, was not a good indicator of time to the first INR, but it was a significant predictor of time to the first INR of more than four (P=.03).
Both the CYP2C9 genotype and the VKORC1 haplotype influenced the required warfarin dose after two weeks of treatment. – by Stacey L. Adams
N Engl J Med. 2008;358:999-1008.
This is another, in a now long series of papers, which suggests that genotypic analysis in individual patients will likely have a significant impact on our ability to properly dose warfarin. That’s critically important with a drug like warfarin, given its narrow therapeutic window, the substantial hazards of over- or under-dosing and the lack of a good alternative. We know that many individuals show significant variability in their required dose, so the ability to look at these two genes that were examined — VKORC1 and CYP2C9 — again, confirms and extends this general knowledge about their involvement in warfarin response. I think that, ultimately, the analysis of these two loci will become a standard approach for judging the most appropriate starting dose for this agent. Essentially, this work has the potential to decrease adverse reactions from warfarin and increase the safety of a drug that we’re all a bit uncomfortable with because of its inherent problems. Such approaches will also be generalizable to many agents, especially those with similarly narrow therapeutic windows.
– James P. Evans, MD, PhD
Director of Clinical Cancer Genetics and the Bryson
Program in Human Genetics
University of North Carolina at Chapel Hill