title: Limitations of S-warfarin truncated area under the concentration-time curve to predict cytochrome P450 2c9 activity.
abstract: OBJECTIVE
  Phenotyping cytochrome P450 (CYP) 2C9 activity with S-warfarin requires extensive blood sampling to characterize area under the concentration-time curve (AUC). This retrospective data analysis was conducted to determine if truncated S-warfarin AUCs can be used to measure CYP2C9 activity.
  
  
  METHODS
  S-warfarin plasma concentrations were obtained from healthy adults (n = 84) genotyped as CYP2C9 extensive metabolizers (EMs) from 6 published studies. Subjects received a single 10 mg oral warfarin dose during baseline and treatment conditions. AUC zero to infinity (AUCINF) and truncated AUCs at 48 h (AUC(48)), at 72 h (AUC(72)) and at 96 h (AUC(96)) were determined by noncompartmental analysis. Equivalence was determined via least squares geometric mean ratios (LS-GMRs) with 90% confidence intervals (CI) within 0.8-1.25.
  
  
  RESULTS
  A lack of equivalence was observed for AUC(48) and AUC(72) compared to AUC(INF) during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC(96) compared to AUC(INF) during all baseline and treatment conditions. Results were consistent across all evaluated AUCs between baseline and treatment without a CYP2C9-mediated drug-drug interaction and during induction with an oral contraceptive. During inhibition with fluvastatin, a lack of equivalence was observed with AUC(INF)(LS-GMR [90%CI] = 1.25 [1.16-1.34]) and AUC(96) (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC(48)(1.15 [1.08-1.22]) and AUC(72) (1.18 [1.11-1.24]).
  
  
  CONCLUSIONS
  S-warfarin truncated AUC(48) and AUC(72) poorly characterize AUC(INF) and are unable to detect weak CYP2C9 inhibition with fluvastatin. S-warfarin phenotyping parameters need to ensure blood sampling of at least 96 h to characterize AUC and thus CYP2C9 activity.
authors.affiliation: Skaggs School of Pharmacy & Pharmaceutical Sciences University of California, San Diego 9500 Gilman Drive, MC 0714, San Diego, CA 9293, USA.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Wu
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001800:Blood Specimen Collection / Q000379:methods; D003276:Contraceptives, Oral / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D003276:Contraceptives, Oral; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases