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 gen, 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.