Physiologically Based Pharmacokinetic Modeling for Mechanistic Analysis of Food Effects: A Case Study with Radotinib.

PURPOSE: Physiologically based pharmacokinetic (PBPK) modeling has emerged as a promising tool for food effect assessment, yet its utility for poorly soluble and poorly permeable compounds has not been fully established. This study aimed to develop a PBPK model for radotinib, a second-generation tyrosine kinase inhibitor, to predict the food effect. METHODS: The model was verified against plasma concentration-time (Cp-time) data obtained from a clinical trial conducted in healthy volunteers who received an oral dose of 400 mg under fasted and fed conditions. Sensitivity analyses were subsequently performed to identify the absorption-related parameters that influence the prediction of food effect. RESULTS: All simulated-to-observed ratios for maximum Cp (Cmax), and area under the Cp-time curve from time zero to infinity (AUCinf) fell within two-fold acceptance criterion under fasted and fed conditions. Simulated geometric mean ratios for the food effect on Cmax and AUCinf were 2.65 and 3.47, which closely recapitulated the observed ratios of 2.65 and 3.49, respectively. Intrinsic solubility and the logarithm of the bile micelle-to-water partition coefficient for neutral species were identified as the primary determinants of food effect prediction. CONCLUSIONS: These findings demonstrate the utility of PBPK modeling for prediction of food effect on radotinib pharmacokinetics.