SCR430, a sorafenib derivative, is an investigational drug exhibiting anti-tumor action. This study aimed to have a mechanistic understanding of SCR430's time-dependent pharmacokinetics (TDPK) through an ex vivo study combined with an in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modeling. A non-compartmental pharmacokinetic analysis was performed after intravenous SCR430 administration in female Sprague-Dawley rats for a control group (no treatment), a vehicle group (vehicle only, 14 days, PO), and a repeated-dosing group (SCR430, 30 mg/kg/day, 14 days, PO). In addition, hepatic uptake and metabolism modulation were investigated using isolated hepatocytes from each group of rats. The minimal PBPK model based on IVIVE was constructed to explain SCR430's TDPK. Repeated SCR430 administration decreased the systemic exposure by 4.4-fold, which was explained by increased hepatic clearance (4.7-fold). The ex vivo study using isolated hepatocytes from each group suggested that the increased hepatic uptake (9.4-fold), not the metabolic activity, contributes to the increased hepatic clearance. The minimal PBPK modeling based on an ex vivo study could explain the decreased plasma levels after the repeated doses. The current study demonstrates the TDPK after repeated dosing by hepatic uptake induction, not hepatic metabolism, as well as the effectiveness of an ex vivo approach combined with IVIVE and PBPK modeling to investigate the TDPK.