Articles
Clinical Pharmacology & Therapeutics (2008); 84, 3, 326–331 doi:10.1038/clpt.2008.10
There is a Corrigendum (September 2008) associated with this Article.
Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
BF Gage1, C Eby2, JA Johnson3, E Deych1, MJ Rieder4, PM Ridker5, PE Milligan1, G Grice6, P Lenzini1, AE Rettie7, CL Aquilante3,8, L Grosso9, S Marsh1, T Langaee3, LE Farnett10, D Voora1,11, DL Veenstra3, RJ Glynn5, A Barrett1 and HL McLeod1,12
- 1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
- 2Department of Laboratory & Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
- 3Department of Pharmacy Practice, University of Florida, Gainesville, Florida, USA
- 4Department of Genome Sciences, University of Washington, Seattle, Washington, USA
- 5Department of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- 6Department of Pharmacy Practice, Saint Louis of Pharmacy, St. Louis, Missouri, USA
- 7Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA
- 8Department of Pharmaceutical Sciences, University of Colorado, Denver, Colorado, USA
- 9Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
- 10Sanofi-Aventis, San Antonio, Texas, USA
- 11Division of Cardiovascular Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- 12Division of Medical Oncology, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
Correspondence: BF Gage, (bgage@im.wustl.edu)
Received 10 October 2008; Accepted 23 December 2008; Published online 27 February 2008.
Abstract
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 m2), 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.
