title: S-Warfarin Limited Sampling Models to Estimate Area Under the Concentration Versus Time Curve for Cytochrome P450 2C9 Baseline Activity and After Induction.
abstract: Phenotyping cytochrome P450 (CYP) 2C9 activity using S-warfarin has routinely required extensive blood sampling over at least 96 hours after dose to estimate the area under the concentration time curve from zero to infinity (AUC). Alternatively, S-warfarin limited sampling models (LSMs) using one or 2 concentration timepoints have been proposed to estimate AUC. This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced-stage cancer patients.
  
  
  
  Plasma S-warfarin concentrations from healthy adults (n = 92) and in advanced-stage cancer patients (n = 22) were obtained from 6 published studies where a single 10 mg dose of oral warfarin was administered at CYP2C9 baseline and induction conditions. S-warfarin observed AUC was determined by noncompartmental analysis, whereas estimated AUC was calculated from the LSMs. Bias and precision were assessed by percent mean prediction error, percent mean absolute error, and percent root mean square error.
  
  
  
  Different results were observed for S-warfarin LSMs in estimating CYP2C9 baseline activity, with most studies resulting in unacceptable bias and precision. The percent mean prediction error, percent mean absolute error, and/or percent root mean square error exceeded acceptable limits for LSMs in patients with advanced-stage cancer and during CYP2C9 induction with lopinavir/ritonavir.
  
  
  
  The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs.
authors.affiliation: *Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UCSD), La Jolla; †Bertino Consulting, Schenectady, New York; ‡Eshelman School of Pharmacy, University of North Carolina at Chapel Hill; §Disposition Safety and Animal Research, Sanofi, Bridgewater, New Jersey; and ¶Section of Clinical Pharmacology, Deptartment of Medicine, The Geisel School of Medicine at Dartmouth and The Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chang
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Sandrine
authors.initials: S
authors.lastname: Turpault
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015982:Bias; D001800:Blood Specimen Collection; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9 / Q000096:biosynthesis / Q000235:genetics*; D016903:Drug Monitoring / Q000379:methods*; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009369:Neoplasms / Q000473:pathology; D010641:Phenotype; D012189:Retrospective Studies; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9