Development of PBPK Model-Based Mechanistic IVIVCs for Long-Acting Injectable Suspensions

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 medications.

Grant Number: 5U01FD008304-02
NIH Institute/Center: FDA
Principal Investigator: DIANE BURGESS