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Due to its narrow therapeutic index and substantial inter-patient variability in clinical response, warfarin represents an ideal drug candidate to benefit from the promise of pharmacogenomic-guided dosing strategies. Consistent with in vitro data, clinical studies have demonstrated that CYP2C9 polymorphisms significantly influence warfarin pharmacokinetics by reducing (S)-warfarin metabolic clearance, consequently lowering maintenance dose requirements and increasing the risk over-anticoagulation during the initiation phase of therapy. Recent data suggest that polymorphisms in genes encoding several pharmacodynamic determinants of the coagulation cascade may also influence warfarin's antithrombotic dose-response. Of these, VKORC1 polymorphisms account for a significant proportion of the inter-individual variability in warfarin dose requirements in all populations evaluated. Collectively, these data suggest that assessment of genetic polymorphisms affecting both warfarin pharmacokinetics and pharmacodynamics could help to predict warfarin dose requirements in patients. Therefore, the promise of pharmacogenomic-guided dosing as a useful strategy to improve clinical outcomes with warfarin therapy appears credible and warrants further investigation.
CB# 7360, Kerr Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Publication date: January 1, 2007
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Current Clinical Pharmacology publishes frontier reviews on all the latest advances in clinical pharmacology. The journal's aim is to publish the highest quality review articles in the field. Topics covered include: pharmacokinetics; therapeutic trials; adverse drug reactions; drug interactions; drug metabolism; pharmacoepidemiology; and drug development. The journal is essential reading for all researchers in clinical pharmacology.