Limitations of S-Warfarin Truncated Area Under the Concentration-Time Curve to Predict Cytochrome P450 2c9 Activity

Jerry      C. Wu; Anne      N. Nafziger; Joseph      S. Bertino; Joseph      D. Ma

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 (AUC_INF) and truncated AUCs at 48 h (AUC₄₈), at 72 h (AUC72) and at 96 h (AUC₉₆) 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 AUC₄₈ and AUC₇₂ compared to AUC_INF during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC₉₆ 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 AUC₉₆ (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC₄₈ (1.15 [1.08-1.22]) and AUC_{72_{(1.18 [1.11-1.24]).

Conclusions: S-warfarin truncated AUC₄₈ and AUCM₇₂ 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.

Keywords:
S-warfarin, cytochrome P450, CYP2C9, phenotyping, drug-drug interactions}}