title: Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R ratios, accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers.
abstract: S-warfarin area under the concentration-time curve (AUC(0- infinity )) and clearance are used as measures of cytochrome p450 (CYP) 2C9 activity. In addition, warfarin S/R ratios are used to assess CYP2C9 activity. The determination of S-warfarin AUC(0- infinity ) requires multiple blood samples. Limited sampling strategy (LSS) is a validated technique that estimates AUC(0- infinity ) using limited blood samples. The objective of this study was to evaluate LSS of S-warfarin concentrations and warfarin S/R ratios to predict S-warfarin AUC(0- infinity ) during CYP2C9 baseline activity and inhibition with fluvastatin. Fifty-one healthy subjects, genotyped as CYP2C9 extensive metabolizers, were administered oral warfarin 10 mg. Blood samples were collected over 96 hours. S-warfarin AUC(0- infinity ) equations were derived from a training set of 20 subjects using multiple linear regression. Validation of the equations used data from the remaining 31 subjects. All derived equations were within acceptable limits for measures of bias and precision. Single-point and two-point S-warfarin concentrations, but not warfarin S/R ratios, were predictive of S-warfarin AUC(0- infinity ) during CYP2C9 baseline activity and inhibition. No correlation was observed between CYP2C9(*)1/(*)1 and (*)1/(*)2 genotypes and either S-warfarin concentrations or warfarin S/R ratios. The equation using two-point S-warfarin concentrations at 24 and 48 hours was the most accurate predictor of S-warfarin AUC(0- infinity ). LSS using S-warfarin concentrations is an efficient and accurate technique to evaluate S-warfarin AUC(0- infinity ) when using warfarin as a CYP2C9 probe drug.
authors.affiliation: PharmD, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Myong-Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rowland
authors.forename: Jooran S
authors.initials: JS
authors.lastname: Kim
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D001800:Blood Specimen Collection; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D013237:Stereoisomerism; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases