(M1230-10-64) PBPK Modeling Coupled with Biorelevant Dissolution to Forecast the Oral Performance of Amorphous Solid Dispersion Formulations

Purpose: Physiologically-based pharmacokinetic (PBPK) modeling is a promising tool for predicting systemic drug exposure and assessing drug–drug interactions. The FDA has advocated for the utilization of new tools and approaches, such as PBPK modeling, to link pharmaceutical quality to clinical performance and speed access to safe and effective generic drugs. PBPK models enable the integration of drug- and formulation-specific properties with physiology, making it a useful tool for biopharmaceutics analyses for orally administered drug products. Evaluation of the impact of food on the PK of an orally administered new drug product is a standard component of the clinical development program. In this study we investigated whether PBPK models can recapitulate the food effect observed for Itraconazole (model drugs from the BCS II class) and explore ways to derive and incorporate biopharmaceutics aspects on the bioavailability. We aimed to leverage the learn-confirm paradigm in drug development to support generic drug product development and assessment. This framework also aims to provide a standardized approach to PBPK modeling that can be used across different drug development programs.

Methods: The study outlines a stepwise approach for PBPK simulation that involves learning and confirming phases. In the learning phase, the model was trained using in vitro dissolution data, and intestinal precipitation was modeled in both open and closed systems. In the confirming phase, simulations were conducted to predict the Sporanox® fasted and fed-state pharmacokinetic profiles, as well as the effect of different fed-state conditions on dissolution and solubility. The PBPK model was validated using external in vitro data and confirmed with clinical data from healthy adults. This methodology provides a comprehensive framework for PBPK modeling of Sporanox® capsule in the fed state and is applicable to other drug development programs.

Results: The study presents a PBPK modeling approach for Sporanox® capsules in the fed state. The PBPK model was developed in a stepwise manner, beginning with the modeling of Sporanox® in vitro dissolution data in different media. Rate of precipitation (k_prec = 1.3 h^-1) estimated using two stage biphasic dissolution was used in the confirmation phase and in the development of full PBPK model of Itraconazole. During the confirmation phase Sporanox® was simulated in fasted conditions and the ratio of the observed and predicted AUC and Cmax was found to be within the acceptable limit. The model was then validated using external data sets, and intestinal precipitation was modeled using biphasic dissolution kinetics. The PK profile of Sporanox® was simulated in healthy adults with and without hypochlorhydria. The model was able to recapitulate the hypochlorhydria condition which results in the reduction of 30-40 % reduction in the AUC. The fed state gastric dissolution was modeled using a segregated transit times function in a static/closed stomach compartment. The effect of lipidic/fatty/oily vehicles on fed state solubility was also considered, along with time-dependent fed gastric pH. Finally, the PBPK model was confirmed by simulating clinical trials in healthy adults under fed state conditions. The ratio of the observed and predicted AUC and C max was found to be within the 2-fold limit. This framework provides a standardized approach to PBPK modeling that can be used across different drug development programs and supports model-informed biowaivers of fed state bioequivalence studies for BCS class II drugs.

Conclusion: The present study describes a step-by-step approach for conducting PBPK modeling of Sporanox® capsules in the fed state. The framework includes learning and confirming phases, where different aspects of PBPK modeling are explored and validated. Overall, the proposed framework provides a standardized approach to PBPK modeling for BCS class II drugs, which could be useful for model-informed biowaivers of fed state bioequivalence studies.

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Acknowledgements:This work was supported by a grant from the Food and Drug Administration

Figure. 1: Modeling intestinal precipitation in vitro: closed systems (A) vs open (B)

Figure. 2: Sporanox® simulation in fasted condition: 100mg (A) & 200mg (B)

Figure. 3: Sporanox capsules 100(A) and 200 (B) mg PK profile in fed condition