SUMMARY/ABSTRACT: Long-acting injectable (LAI) suspensions represent a class of complex drug products administered either intramuscularly or subcutaneously and characterized by depot formation that results in prolonged release profiles. Despite their therapeutic potential, LAI suspensions are relatively underdeveloped, partly due to the limited understanding of the complex interplay between the formulation and the physiological response at the depot site. Furthermore, there is an absence of generic versions for many commercial LAI suspensions, despite expiration of patents and exclusivity rights. This can be explained by the limited understanding of how critical formulation attributes (CQAs) affect the in vivo behavior of LAI suspensions. Challenges in conducting bioequivalence (BE) studies and the absence of robust in vitro-in vivo correlations (IVIVCs) are additional burdens to LAI generic development. Accordingly, additional research is needed to enhance the understanding of interactions between formulation CQAs and the physiological response at the depot site, to develop in silico mechanistic IVIVCs. To address these challenges, this research aims to comprehensively investigate the interplay between formulation CQAs and physiological factors at the local site to accurately predict in vivo drug release using physiologically based pharmacokinetic (PBPK) models. To achieve this goal, the offerors plan to: (1) Perform a thorough investigation into the complex relationships among the physicochemical properties of Q1Q2 equivalent formulations of Depo Provera 150® and their impact on in vitro release. (2) Understand how the physicochemical properties of Q1Q2 equivalent formulations of Depo Provera 150® and the local tissue physiology impact in vivo release. (3) Develop model-based mechanistic IVIVCs for Depo Provera 150® in GastroPlus® considering both the physiological response and the product morphometrics at the local site. (4) Understand how the complex interplay between formulation physicochemical properties and physiological properties at the local site impacts in vitro and in vivo performance of Depo SubQ Provera 104® and refine previously developed preclinical IVIVCs. This research represents a significant effort to reveal the intricate relationships between formulation properties and injection site physiology, providing insight into BE approaches for LAI suspensions. The in vitro and in vivo data generated will provide a comprehensive understanding of physicochemical and physiological interactions, allowing development of robust and reliable PBPK model-based mechanistic IVIVCs for LAIs. This proposal builds on and extends previous investigations by Dr. Burgess’ laboratory and Simulations Plus, in partnership with the US FDA. Ultimately, this work will establish BE recommendations thus ensuring the availability of safe and economical generic LAI products, benefiting public health by providing the American people access to essential medica...