Pharmacokinetic Modeling of Warfarin І - Model-based Analysis of Warfarin Enantiomers with a Target Mediated Drug Disposition Model Reveals CYP2C9 Genotype-dependent Drug-drug Interactions of S-Warfarin.

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The objective of this study is to characterize the impact of CYP2C9 genotype on warfarin drug-drug interactions when warfarin is taken together with fluconazole, a cytochrome P450 (CYP) inhibitor, or rifampin, a CYP inducer with a nonlinear mixed effect modeling approach. A target mediated drug disposition model with a urine compartment was necessary to characterize both S-warfarin and R-warfarin plasma and urine pharmacokinetic profiles sufficiently. Following the administration of fluconazole, our study found subjects with CYP2C9 *2 or *3 alleles experience smaller changes in S-warfarin CL compared with subjects without these alleles (69.5%, 64.8%, 59.7% and 47.8% decrease in subjects with CYP2C9 *1/*1, *1/*3, *2/*3 and *3/*3 respectively). Whereas, following the administration of rifampin, subjects with CYP2C9 *2/*3 or CYP2C9 *3/*3 experience larger changes in S-warfarin CL compared with subjects with at least one copy of CYP2C9 *1 or *1B (115%, 111%, 119%, 198% and 193% increase in subjects with CYP2C9 *1/*1, *1B/*1B, *1/*3, *2/*3 and *3/*3 respectively). The results suggest different dose adjustments are potentially required for patients with different CYP2C9 genotypes if warfarin is administered together with CYP inhibitors or inducers. Significance Statement The present study found a target mediated drug disposition model is needed to sufficiently characterize the clinical pharmacokinetic profiles of warfarin racemates under different co-treatments in subjects with various CYP2C9 genotypes, following a single dose of warfarin administration. The study also found S-warfarin, the pharmacologically more active ingredient in warfarin, exhibits CYP2C9 genotype-dependent drug-drug interactions, which indicates the dose of warfarin may need to be adjusted differently in subjects with different CYP2C9 genotypes in the presence of drug-drug interactions.