학술논문
Integration of genetic, clinical, and INR data to refine warfarin dosing
Document Type
Author
Lenzini, P.; Wadelius, Mia; Kimmel, S.; Anderson, J. L.; Jorgensen, A. L.; Pirmohamed, M.; Caldwell, M. D.; Limdi, N.; Burmester, J. K.; Dowd, M. B.; Angchaisuksiri, P.; Bass, A. R.; Chen, J.; Eriksson, N.; Rane, A.; Lindh, J. D.; Carlquist, J. F.; Horne, B. D.; Grice, G.; Milligan, P. E.; Eby, C.; Shin, J.; Kim, H.; Kurnik, D.; Stein, C. M.; McMillin, G.; Pendleton, R. C.; Berg, R. L.; Deloukas, P.; Gage, B. F.
Source
Clinical Pharmacology and Therapeutics. 87(5):572-578
Subject
Language
English
ISSN
0009-9236
1532-6535
1532-6535
Abstract
Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.