title: Evaluation of methods for achieving stable INR in healthy subjects during a multiple-dose warfarin study.
abstract: OBJECTIVE
  No consistent method is available for finding stable warfarin maintenance doses and fast stabilization of international normalized ratio (INR) values among healthy subjects in experimental warfarin interaction studies. Using data from an earlier study that targeted a stable INR of 1.5-2.0 to test an interaction, we retrospectively evaluated potential dosing algorithms using all methods available to us to decrease the time needed for INR stabilization, which could be useful for future interaction studies in healthy subjects.
  
  
  METHODS
  Published pharmacogenetic and clinical dosing algorithms used to initiate pharmacotherapy with warfarin were applied, predicted doses and actual doses were compared by regression analysis, and concentration-time profiles of S-warfarin were simulated using SimCYP® software.
  
  
  RESULTS
  No demographic variables were significantly associated with time to reach a stable, low-intensity INR in this population of relatively young, healthy subjects. Predicted and actual doses were positively correlated for the pharmacogenetic algorithm, but not for the clinical algorithm. INR levels and S-warfarin concentrations were associated with CYP2C9 and VKORC1 genotypes.
  
  
  CONCLUSIONS
  Induction to a pharmacodynamic steady state for warfarin for future multiple-dose warfarin drug-interaction studies in healthy volunteers may be predicted using a pharmacogenetic-based dosing algorithm. Simulations revealed that the desired subtherapeutic INR level may be achieved by reducing the predicted dose by approximately 15%. Further study is needed to assess the applicability of this approach to decrease attrition rates and the time needed to reach INR stabilization.
authors: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. chappelljc@lilly.com
authors: Jill C
authors: JC
authors: Chappell
authors: Gemma
authors: G
authors: Dickinson
authors: Malcolm I
authors: MI
authors: Mitchell
authors: Harry
authors: H
authors: Haber
authors: Yan
authors: Y
authors: Jin
authors: Evelyn D
authors: ED
authors: Lobo
mesh_terms: D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases