(T-036) Leveraging PBPK Modeling for Bioavailability Enhancement: Insights from In Vitro Dissolution and Cocrystallization Studies

Ana Karolina Goes – Pharmacy – Universidade Estadual do Centro-Oeste (UNICENTRO); Amira Soliman – Pharmaceutics – Center for Pharmacometrics and Systems Pharmacology, University of Florida; Paulo Olivera – Pharmacy – Universidade Estadual do Centro-Oeste (UNICENTRO),; Natalia de Moraes – Pharmaceutics – Center for Pharmacometrics and Systems Pharmacology, University of Florida

Objectives: Pharmaceutical cocrystals are typically formed by combining an active pharmaceutical ingredient with a coformer to enhance drug solubility, stability and dissolution, thereby improving absorption and bioavailability while preserving pharmacological properties. Cocrystallization has emerged as a promising strategy to address solubility challenges, particularly for drugs with low solubility and high permeability. Ketoconazole (KTZ), a Biopharmaceutics Classification System (BCS) Class II drug, exhibits dissolution-limited absorption and variable oral bioavailability. As a weak dibasic drug, its dissolution is facilitated by acidic gastric pH. Leveraging the in vitro dissolution enhancement of KTZ through cocrystallization with succinic acid (SA) as a coformer, we aim to apply physiologically based pharmacokinetic (PBPK) modeling to predict the in vivo dissolution and bioavailability enhancement of KTZ-SA cocrystal in populations with varying gastric acidity.

Methods: A comprehensive PBPK model for KTZ was developed using SimCYP™ V24. Initially, KTZ in vitro solubility in simulated and biorelevant media, along with dissolution profiles, were utilized to predict product-specific parameters, including bile: micelle partition coefficients (log Km:w), and product particle size distribution (P-PSD) using the SIVA toolkit. Intrinsic clearance values were adjusted to accurately reflect KTZ's nonlinear in vivo clearance for doses ranging from 100 to 800 mg. The PBPK model was then verified using observed clinical data. For the KTZ-SA cocrystal, solubility parameters, P-PSD, and solubility factor were estimated based on in vitro experimental data. These values were then incorporated into the PBPK model to predict the in vivo bioavailability of healthy and achlorhydric populations.

Results: By integrating the in vitro solubility and dissolution profiles, and the nonlinear elimination, PBPK simulations were carried out to predict plasma concentration-time profiles of KTZ in healthy volunteers. The developed KTZ-PBPK model was verified using plasma concentration-time profiles and pharmacokinetic (PK) metrics in healthy volunteers, achieving a predicted/observed area under the concentration-time curve (AUC) ratio within the range of 0.5 to 1.8. Our simulations showed a reduced exposure to KTZ under achlorhydric conditions (AUC₀-₂₄ = 1.11 µg·h/mL; Cmax = 0.18 µg/mL; Fa < 0.2), as compared to healthy subjects (AUC₀–₂₄ = 12.68 µg·h/mL; Cmax = 4.56 µg/mL; Fa = 0.8). In contrast, the KTZ-SA cocrystal achieved consistently high systemic exposure in both healthy (AUC₀–₂₄: 17 µg·h/mL; Cmax = 6.20 µg/mL) and achlorhydric populations (AUC₀–₂₄: 16.9 µg·h/mL; Cmax = 5.26 µg/mL).

Conclusions: The application of PBPK modeling has demonstrated the potential of KTZ-SA cocrystal to significantly enhance the bioavailability in populations with achlorhydria-related disparity, overcoming the limitations posed by variable gastric acidity. The findings support further exploration and development of pharmaceutical cocrystals to optimize drug delivery and therapeutic outcomes.

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Keywords: Cocrystallization, Bioavailability, Ketoconazole