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Development and verification of in vitro integrated mechanistic population-based PBPK model framework towards virtual bioequivalence assessment of locally acting drug products in the GI tract

Award Number: U01FD007662
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Development and verification of in vitro integrated mechanistic population-based PBPK model framework towards virtual bioequivalence assessment of locally acting drug products in the GI tract - PROJECT SUMMARY Lower-cost generic drugs generated approximately $2.2 trillion in savings to the US healthcare system in the past decade. Therefore, generic drugs play a pivotal role in the sustainability of the US health system. A generic drug is approved on the basis of sufficient demonstration of sameness to the corresponding brand-name drug. Critical evidence for approval is bioequivalence (BE). Pharmacokinetics (PK) is the most commonly used BE endpoint for systemically acting drugs since systemic exposure is upstream of the respective site of action. However, the PK-based approach, if measurable, may not be sufficient for demonstrating BE for locally acting drugs if there is a non-linear relationship between local and systemic exposures. Furthermore, systemic variability may bias the retrospective assessment of local drug exposure. To the best of our knowledge, concordance or discordance between systemic and local drug exposures has not been adequately addressed in public domain. Quantitative methods and modeling have been widely used in the realm of new drug discovery and development to inform more efficient and cost-effective development programs. Physiologically-based pharmacokinetic (PBPK) modeling is one of the key tools under the overarching umbrella of quantitative models. PBPK models are an effective tool to integrate information about the product characteristics, the physiology of the individual subject, and the variability among subjects within a population to simulate the local bioavailability throughout the GI tract and subsequent systemic disposition of the drug without conducting in vivo PK studies. PBPK models have shown promise in supporting generic drug development and regulatory decision-making, since, under a model-integrated evidence perspective, it enables the leveraging of all prior knowledge generated to support the regulatory approval of the respective brand-name drug product. We will generate, analyze and integrate innovative in vitro data and PBPK modeling to assess the concordance level between systemic and local drug exposures for drugs targeting the GI tract. The emerging model integrated evidence framework will enable BE assessment at local and systemic levels. This will be done considering healthy subjects and Crohn’s disease patients to test the hypothesis that (virtual) BE studies in healthy adults can be safely generalized across target patient populations. We have excellent in vitro testing (and model-based data analysis, i.e. SIVA toolkit) and PBPK modeling capabilities, along with unique replicate BE, PK, luminal drug concentration data sets. Once established, this framework can also be extended to integrate prediction of local exposure and intestinal epithelium life span to ultimately predict the time course of pharmacodynamic effects of enterocyte-targeting drugs by integrating the nested enzyme-within-enterocyte turnover model into the mechanistic M-ADAM model in the Simcyp™ simulator.


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 = $0 )
2025	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Food and Drug Administration Research	000	2	7/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Food and Drug Administration Research	000	2	9/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $299,991 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Food and Drug Administration Research	000	2	8/24/2023	NON-COMPETING CONTINUATION	$299,991
														Subtotal = $299,991

Issue Date FY: 2022 ( Subtotal = $299,986 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Food and Drug Administration Research	000	1	9/23/2022	NEW	$299,986
														Subtotal = $299,986

Grand Total All Awards = $599,977

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Development and verification of in vitro integrated mechanistic population-based PBPK model framework towards virtual bioequivalence assessment of locally acting drug products in the GI tract

Award Number: U01FD007662

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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