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Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
Author(s) -
Gage BF,
Eby C,
Johnson JA,
Deych E,
Rieder MJ,
Ridker PM,
Milligan PE,
Grice G,
Lenzini P,
Rettie AE,
Aquilante CL,
Grosso L,
Marsh S,
Langaee T,
Farnett LE,
Voora D,
Veenstra DL,
Glynn RJ,
Barrett A,
McLeod HL
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.10
Subject(s) - pharmacogenetics , vkorc1 , warfarin , cyp2c9 , dosing , medicine , clinical pharmacology , cohort , pharmacology , biology , genetics , genotype , atrial fibrillation , gene , cytochrome p450 , metabolism
Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.