PBPK model of carbamazepine and its metabolite for bioequivalence assessment: prioritizing early exposure and single-dose study designs.

Abstract

A physiologically based pharmacokinetic (PBPK) model for carbamazepine (CBZ) was calibrated against an intravenous clinical dataset. Absorption was characterised using the Advanced Dissolution, Absorption and Metabolism (ADAM) model coupled to the diffusion layer model and a particle population balance framework, incorporating formulation-specific particle size distributions. Model verification was performed against 36 clinical datasets spanning single-dose (SD), and multiple-dose (MD) oral administrations across multiple dosage forms. The model was benchmarked against a published CBZ PBPK model (Yin et al., 2024) and further verified through five drug-drug interaction scenarios involving cytochrome P450 modulation. Virtual bioequivalence trials (2 × 2 crossover, n = 24, 100 replicates) were conducted for oral suspensions and immediate-release tablets to compare SD and MD discriminatory power, and to evaluate partial AUC from 0 to 2 h (pAUC0-2h) against conventional bioequivalence metrics. The model matched or outperformed Yin et al. across all scenarios. SD designs consistently demonstrated superior discriminatory power over MD designs (contradicting the proposal that MD studies are more discriminating for autoinducing CBZ); despite autoinduction progressively increasing apparent clearance, formulation-related differences in absorption were attenuated at steady state. pAUC0-2h showed higher sensitivity than Cmax for detecting absorption rate differences. These findings support SD study designs for CBZ bioequivalence assessment and identify pAUC0-2h as a clinically meaningful complementary metric.