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

Abstract

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.

Keywords: drug-drug interactions; genetic polymorphism; pharmacokinetic modeling.

Fig. 1.

Study Design Diagram. Each subject went through 3 study periods (upper dark blue section). Period 1 (red box), single 10 mg dose of warfarin. Periods 2 and 3 in crossover (yellow box), each subject was pretreated with either 400 of mg fluconazole or 300 mg of rifampin once daily for 7 consecutive days, followed by a single 10 mg dose of warfarin and continuous treatment with either 400 mg of fluconazole or 300 mg of rifampin once daily through the sampling phase. Notes: q.d.: Once daily.

Fig. 2.

PK model structure for S- and R-warfarin. Notes: Periph: peripheral; Cent: central.

Fig. 3.

PK profiles for S-warfarin in plasma (A) and urine (B) and R-warfarin in plasma (C) and urine (D). All the PK profiles are stratified by co-treatments. Colors represent different CYP2C9 genotypes as shown in figure legends. Plots are on log scales. Points represent mean and error bars represent 95% confidence intervals.

Fig. 4.

VPCs for S-warfarin PK profiles in plasma (A) and urine (B). Blue dots represent the observations. Red solid lines represent the medians of model predicted concentrations. The upper and lower red dashed lines represent the 10^th and 90^th percentiles of the model predicted concentrations, respectively. The figure is stratified by genotypes and co-treatments. The black dashed lines represent the LLOQ for S-warfarin (0.67 ng/ml). No observations were collected from CYP2C9 *1B/*1B subjects and treated with warfarin plus fluconazole. Note: Warf: warfarin; Flu: fluconazole; Rif: rifampin; *1/*1: CYP2C9 *1/*1; *1B/*1B: CYP2C9 *1B/*1B; *1/*3: CYP2C9 *1/*3; *2/*3: CYP2C9 *2/*3; *3/*3: CYP2C9 *3/*3.

Fig. 5.

VPCs for R-warfarin PK profiles in plasma (A) and urine (B). Blue dots represent the observations. Red solid lines represent the medians of model predicted concentrations. The upper and lower red dashed lines represent the 10^th and 90^th percentiles of the model predicted concentrations, respectively. The figure is stratified by genotypes and co-treatments. The black dashed lines represent the LLOQ for R-warfarin (0.67 ng/ml). No observations were collected from CYP2C9 *1B/*1B subjects and treated with warfarin plus fluconazole. Note: Warf: warfarin; Flu: fluconazole; Rif: rifampin; *1/*1: CYP2C9 *1/*1; *1B/*1B: CYP2C9 *1B/*1B; *1/*3: CYP2C9 *1/*3; *2/*3: CYP2C9 *2/*3; *3/*3: CYP2C9 *3/*3.

Fig. 6.

Genotype-dependent CL changes of S-warfarin following the administration of fluconazole (A) and rifampin (B). The dots and error bars represent the typical values and 95% CIs, respectively. The 95% CIs are constructed with RSE as shown in Table 1 assuming a symmetric normal distribution.