Establishing clinically relevant dissolution specifications for prodrug bioequivalence risk assessment: Integration of a dissolution/permeation system with physiologically based biopharmaceutics modeling in abiraterone acetate

Prodrugs with enzymatic activation requirements, such as the weakly basic biopharmaceutical classification system (BCS) class IV compound abiraterone acetate (ABA), face considerable bioequivalence (BE) risks owing to their pH-dependent solubility, food effects, and variable intestinal hydrolysis. This study established clinically relevant dissolution specifications for ABA using biorelevant dissolution and physiologically based biopharmaceutics modelling (PBBM). Two dissolution methods, two-stage (gastrointestinal transfer simulation) and single-phase (biorelevant media), were evaluated under fasted and fed conditions. Clinical BE studies revealed non-BE for formulation A (fasted, N = 39) but compliance for formulation B (fasted/fed, N = 40). Two-stage dissolution highlighted supersaturation dynamics, with fed-state media (FeSSIF-V2) enhancing solubility by >10-fold compared to fasted conditions. Although this method is biopredictive, its complexity limits its practicality. Single-phase dissolution using biorelevant media balances discriminative power and operational feasibility for quality control. Permeability studies identified the active metabolite abiraterone as the absorption driver (apparent permeability coefficient: 1.55 × 10⁻⁵ vs. 8.91 × 10⁻⁶ cm/s for ABA). PBBM integrating hydrolysis kinetics, food effects, and first-pass metabolism predicted clinical pharmacokinetics with a prediction error of <20 %. Virtual BE trials defined a dissolution “safe space” for bioequivalence under both fasted/fed states. This study demonstrates that combining biorelevant dissolution with mechanistic modelling mitigates BE risks for high-variability prodrugs. This single-phase approach offers a scalable and physiologically aligned strategy for guiding the generic development of complex formulations with food-dependent absorption variability.