To explore the dose optimization of imatinib in children with liver dysfunction based on the PBPK model

Aims: This study aimed to characterize the pharmacokinetics of imatinib in paediatric patients with hepatic impairment, a population for whom evidence-based dosing guidance is currently lacking, in order to inform safe and effective prescribing across a range of clinical scenarios. Methods: Using PK-Sim® software, we integrated physiological, physicochemical, and clinical pharmacokinetic data to develop a physiologically based pharmacokinetic (PBPK) model for imatinib in adults with normal hepatic function. This model was subsequently extrapolated to predict imatinib disposition in children with hepatic impairment, enabling estimation of age- and liver-function-specific doses that maintain plasma concentrations within the therapeutic window. Results: A PBPK framework was first established and verified against clinical pharmacokinetic data obtained from adults and children with varying degrees of hepatic impairment. The final paediatric model, stratified into 12 age- and liver-function subgroups, predicted exposure to imatinib that rose progressively as hepatic function declined. To maintain concentrations within the therapeutic window, dose recommendations were derived: 260–340 mg/m ² /d. For children with normal hepatic function, 260 mg/m ² /d. For mild or moderate impairment, and 200 mg/m ² /d. For severe hepatic dysfunction. Conclusion: Hepatic impairment in children significantly elevates systemic imatinib exposure, resulting in a corresponding increase in adverse-event incidence.