Integration of genetic, clinical, and INR data to refine warfarin dosing

P. Lenzini, M. Wadelius, S. Kimmel, J. L. Anderson, A. L. Jorgensen, M. Pirmohamed, M. D. Caldwell, N. Limdi, J. K. Burmester, M. B. Dowd, P. Ngchaisuksiri, A. R. Bss, J. Chen, N. Eriksson, A. Rane, J. D. Lindh, J. F. Carlquist, B. D. Horne, G. Grice, P. E. MilliganC. Eby, J. Shin, H. Kim, D. Kurnik, C. M. Stein, G. McMillin, R. C. Pendleton, R. L. Berg, P. Deloukas, B. F. Gage

Research output: Contribution to journalArticlepeer-review

187 Scopus citations

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): 7.0mg/week) and the pharmacogenetic algorithm had an R 2 of 63% (MAE: 5.5mg/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.

Original languageEnglish
Pages (from-to)572-578
Number of pages7
JournalClinical pharmacology and therapeutics
Volume87
Issue number5
DOIs
StatePublished - May 2010

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