Chen_2026_Front.Pharmacol_17_1801897

BACKGROUND: Irinotecan (CPT-11) is a prodrug that is bioactivated to SN-38, which is primarily cleared via UGT1A1-mediated glucuronidation. Its complex metabolism, which also involves CYP3A-mediated oxidation, makes irinotecan highly susceptible to enzyme-mediated drug-drug interactions (DDIs). This study aimed to develop and qualify an adult whole-body physiologically based pharmacokinetic (PBPK) model of irinotecan and its metabolites (SN-38, SN-38G, and APC) to predict systemic pharmacokinetics and UGT1A1/CYP3A-mediated DDIs. METHODS: An adult middle-out PBPK model was implemented in Simcyp(a), integrating key pathways for carboxylesterase (CES) -mediated activation, UGT1A1/UGT1A9-driven glucuronidation, and CYP3A4/5-mediated oxidation. The model was calibrated using 175-300 mg/m(2) monotherapy data and was validated across a 33-750 mg/m(2) dose range, including drug-drug interactions with ketoconazole, sorafenib, and lopinavir/ritonavir. RESULTS: Most observed irinotecan and SN-38 concentrations fell within the fifth-95th percentile prediction intervals, and dose-exposure slopes were close to unity. Across monotherapy evaluations, 54/56 (96.4%) comparisons of maximum concentration (C(max)) and area under the concentration-time curve (AUC) met the 2-fold acceptance criterion. The model further captured the direction and magnitude of exposure changes across all inhibitor scenarios, with CPT-11 and SN-38 exposure ratios remaining within acceptable limits, although APC exposure was overpredicted in the ketoconazole scenario. CONCLUSION: The mechanistically informed and validated whole-body PBPK model reliably describes dose-dependent irinotecan and SN-38 pharmacokinetics and UGT1A1/CYP3A-mediated drug-drug interactions. This framework provides a clinically relevant tool for enzyme-mediated DDI risk assessment and for exploratory simulation of dose-exposure relationships under standard irinotecan regimens.