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

Award Number: U01FD008304
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $250,000 )
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Food and Drug Administration Research	000	2	8/27/2025	NON-COMPETING CONTINUATION	$250,000
														Subtotal = $250,000

Issue Date FY: 2024 ( Subtotal = $300,000 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Food and Drug Administration Research	000	1	9/2/2024	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $550,000

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

Award Number: U01FD008304

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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