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Title: Integration of genetic, clinical, and INR data to refine warfarin dosing
Authors: 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. Milligan
C. Eby
J. Shin
H. Kim
D. Kurnik
C. M. Stein
G. McMillin
R. C. Pendleton
R. L. Berg
P. Deloukas
B. F. Gage
Washington University in St. Louis
Uppsala Universitet
University of Pennsylvania
Intermountain Medical Center
University of Liverpool
Marshfield Clinic
University of Alabama
Clinical Pharmacy Cardiac Risk Service
Mahidol University
Hospital for Special Surgery - New York
Akademiska Sjukhuset
Karolinska Institutet
St. Louis College of Pharmacy
Inje University
Vanderbilt University
University of Utah
Wellcome Trust Sanger Institute
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-May-2010
Citation: Clinical Pharmacology and Therapeutics. Vol.87, No.5 (2010), 572-578
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 R2of 48% (median absolute error (MAE): 7.0mg/week) and the pharmacogenetic algorithm had an R2of 63% (MAE: 5.5mg/week) in the derivation set (N = 969). In independent validation sets, the R2was 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.
ISSN: 15326535
Appears in Collections:Scopus 2006-2010

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