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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

From the Clinical Pharmacology Research Center (Dr. Ma, Dr. Nafziger, Dr. J. S. Kim, Dr. Bertino), Department of Medicine (Dr. Nafziger, Dr. Bertino), and Department of Pharmacy Services (Dr. Bertino), Bassett Healthcare, Cooperstown, New York; School of Pharmacy, University of North Carolina, Chapel Hill (Dr. Kashuba, Ms. Rowland); Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland (Dr. M.-J. Kim); and the Division of Pediatric Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital and Clinics, Kansas City, Missouri (Dr. Gaedigk).

S-warfarin area under the concentration-time curve (AUC_0-) 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- requires multiple blood samples. Limited sampling strategy (LSS) is a validated technique that estimates AUC_0- 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- 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- 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- 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-. LSS using S-warfarin concentrations is an efficient and accurate technique to evaluate S-warfarin AUC_0- when using warfarin as a CYP2C9 probe drug.

Key Words: CYP2C9 • S-warfarin • warfarin S/R ratios • limited sampling strategy • drug metabolism

Address for reprints: Joseph S. Bertino Jr., PharmD, FCP, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394.

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