Prediction of Fesoterodine PK in Japanese Population using Physiologically-Based Pharmacokinetic Modeling

抄録

【Objective】The objective of this presentation is to investigate the predictability of fesoterodine PK in Japanese population using physiologically-based pharmacokinetic (PBPK) model developed based on Western clinical data.

【Methods】Fesoterodine is a once-daily oral medication at recommended doses of 4 or 8 mg for the treatment of overactive bladder. Fesoterodine is a prodrug which rapidly absorbed in humans and immediately and extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT), which is further metabolized to inactive metabolites via CYP2D6 and CYP3A4. PBPK model for fesoterodine was developed and verified using 5-HMT data obtained from Western clinical studies to predict drug-drug interaction with mirabegron which is a moderate time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A.¹⁾

In this study, we applied the previously developed PBPK model to predict 5-HMT PK in Japanese population following fesoterodine dosing using Simcyp Version 18 (Sheffield, UK). The predicted 5-HMT PK results were compared with the observed data in Japanese subjects (all CYP2D6 EM) to evaluate the performance of PBPK model to predict PK in other ethnic populations.

【Result・Discussion】The predicted 5-HMT plasma concentrations (mean and the 90% confidence interval) were comparable to those observed individual plasma concentrations in Japanese population. The ratio (predicted/observed) of AUC_inf and C_max values (geometric mean) were all within 1.3. These results suggest the PBPK model for fesoterodine performs well to predict PK in Japanese population.

【Conclusion】PBPK model for fesoterodine developed and verified based on Western data can reasonably describe the 5-HMT PK in Japanese population.

【Reference】1) Lin J, Goosen TC, Tse S, et al. Physiologically based pharmacokinetic modeling suggests limited drug-drug interaction for fesoterodine when coadministered with mirabegron. J Clin Pharmacol 2019;59(11):1505-18