Physiologically Based Pharmacokinetic Modeling of Lenvatinib to Support Dosing Optimization in Chinese Population.

PURPOSE: Lenvatinib is an orally active, targeted tyrosine kinase inhibitor that demonstrates significant clinical efficacy in liver cancer but is associated with a high incidence of adverse reactions. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict lenvatinib exposure in European and Chinese populations and in patients with hepatic impairment, thereby providing a basis for individualized dosing strategies. METHODS: A PBPK model was developed to characterize the pharmacokinetics of lenvatinib in European and Chinese populations and to predict its pharmacokinetic profiles in healthy individuals and patients with hepatic impairment. Additionally, the effect of rifampicin on lenvatinib pharmacokinetics was investigated. The developed PBPK model was validated by comparing predicted plasma concentrations with observed data from clinical studies. FINDINGS: The model accurately described the observed pharmacokinetic profiles across all investigated regimens. Single-dose rifampicin (P-gp inhibition) increased the Cmax and AUC0-∞ of lenvatinib by 28% and 31%, respectively. The predicted AUC0-∞ values for Chinese patients with normal hepatic function and with Child-Pugh A (CP-A), CP-B, and CP-C hepatic impairment were 1106, 1488, 1827, and 1933 µg/h/mL, respectively. IMPLICATIONS: The PBPK model developed in this study enables a more accurate description of lenvatinib pharmacokinetics in European and Chinese populations, as well as in patients with hepatic impairment, and supports the development of individualized dosing recommendations.