Enhancing bioavailability of a weakly basic drug through cocrystallization: PBPK modeling of ketoconazole-succinic...

Pharmaceutical cocrystals, formed by combining an active pharmaceutical ingredient (API) with a suitable coformer, offer a promising strategy to enhance drug solubility, stability, and dissolution, thereby improving absorption and bioavailability without altering pharmacological properties. This approach is particularly advantageous for poorly soluble drugs such as ketoconazole (KTZ), a BCS Class II compound characterized by dissolution-limited absorption and variable oral bioavailability. As a weak dibasic drug, KTZ exhibits pH-dependent dissolution, which was favored under acidic gastric conditions. To overcome the pH-dependent dissolution, a cocrystal of KTZ with succinic acid (SA) was developed and a physiologically based pharmacokinetic (PBPK) approach informed by in vitro solubility and dissolution data was used to predict KTZ plasma concentration profiles, following administration of KTZ or KTZ-SA cocrystal. The developed PBPK model was verified, with a predicted/observed AUC ratio within a 2-fold range for KTZ. The model successfully captured the reduced exposure to KTZ when administered with omeprazole. PBPK simulations demonstrated a reduced KTZ exposure following a 200 mg dose under achlorhydric conditions (AUC: 1.1 µg·h·mL-1) or with omeprazole administration (AUC: 3.1 µg·h·mL-1), compared to healthy subjects (AUC: 12.2 µg·h·mL-1). In contrast, KTZ-SA cocrystal achieved consistently similar exposure in healthy subjects (AUC: 17.2 µg·h·mL-1), achlorhydric populations (AUC: 18.6 µg·h·mL-1), or when coadministered with omeprazole (AUC: 16.9 µg·h·mL-1). This model-based approach has demonstrated the potential of KTZ-SA cocrystal to enhance bioavailability in populations with achlorhydria-related disparities, effectively addressing the challenges posed by variable gastric acidity. The findings support the development of pharmaceutical cocrystals to optimize drug delivery and maximize therapeutic outcomes.