Prediction of Warfarin-Sorafenib Interaction in Japanese Patients Using a Population Pharmacokinetic-Pharmacodynamic Model

Abstract

Backgrounds: The anticoagulant activity of warfarin (R/S-WF) is due mainly to S-WF, which is primarily metabolized by CYP2C9. Previous reports have presented an increase in the International Normalized Ratio (INR) after concomitant administration of WF with sorafenib (SF), a tyrosine kinase inhibitor. However, few studies have focused on quantitative prediction of this INR increase. Objectives: We attempted to predict SF/S-WF concentrations, INR, and the optimal dose of WF in the presence of SF for Japanese patients, based on the metabolic interaction between WF and SF related to CYP2C9 inhibition. Methods: The previous population PK model of SF in the literature was employed to predict the SF concentration. The inhibition constant of SF for S-WF metabolism was determined in in vitro. The unbound fraction of SF in the liver was estimated using the published equation. The competitive inhibition model between WF and SF was incorporated into previously reported population PK-PD models of S-WF to predict the S-WF concentrations and INR. Based on these data, a population PK-PD model describing the interaction between WF and SF was developed using NONMEM. Clinical data and INR values were collected from the literature and used for the model evaluation. Results: The observed time course of INR retrieved from a patient given WF and SF was mostly within the 90% range of the predicted values. We predicted the SF/S-WF concentrations and INR after administration of WF (3 mg/d) alone and WF (3 mg/d) + SF (400 mg/d). It was found that the mean values of S-WF concentration and INR at steady state were 4.8 and 1.9 times greater in the presence of SF with WF, respectively, than those with WF alone. The predicted S-WF concentrations and INR after reduction in the WF dose in the presence of SF did not differ clinically among the regimens (WF 3 mg/d, WF 0.75 mg/d + SF 400 mg/d and WF 0.5 mg/d + SF 400 mg/d) (Figure 1). Conclusions: These results suggest that a reduction in the daily dose of WF (e.g., from 3 mg to 0.5 mg) might be mandatory when WF and SF are administered concomitantly.