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From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions

Award Number: U01FD008388
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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From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions - From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions – Project Abstract The findings from this project will enhance our comprehension of how food and gastric pH affects the release of drugs from ASDs, and how the variability arising from differences in formulations and manufacturing can impact upon in vivo performance. This project will generate Tiny-TIMsg data on a series of amorphous solid dispersion (ASD) drug products under fasted; fed and reduced gastric pH conditions and correlate this in vitro data to in vivo clinical data. In the second step, a mechanistic modeling-based methodology will be employed to link the in vitro dissolution obtained in the Tiny-TIMsg system to the in vivo performance of ASD drug products. Using this in silico model, clinical performances of ASD formulation variants will be simulated, and virtual BE (VBE) conducted to assess the impact of formulation and manufacturing process modification on API’s exposure. The series of ASD drug products will be carefully selected to ensure that there is diversity in products based on: method of manufacture; excipient composition and the ratio of stabilizing polymer:API. Access to clinical data is critical in the selection of products hence the initial focus will be on the identification of relevant data sets. All products to be tested will be interrogated to identify data on degree of solubility enhancement required; pH dependent solubility and reported food effect. Where formulations are not commercially available they will be manufactured to match reported parameters using dissolution matching as the primary target. Output data from the Tiny-TIMsg will report the ratio of bioaccessible dose in either the fed or the reduced gastric pH state to the fasted state; this will be correlated to the clinical data of the ratio of the AUC in the fed or the reduced gastric pH state to the fasted state. Each formulation’s performance in the Tiny-TIMsg will be closely interrogated to identify the kinetics of precipitation to mechanistically understand ASD performance. The closely controlled and reproducible nature of Tiny-TIMsg will enable discrimination at a level not possible with pre- clinical or clinical testing; hence the ability to discriminate between formulations and identify risks associated with food or reduced gastric pH in the prediction of in vivo outcomes. Coupling the Tiny-TIMsg data to PBPK models will support formulation development and minimize future clinical testing thus accelerating the speed of development of safe and effective medicines. The developed and validated workflow will help to establish scientific and regulatory standards for supporting innovative development of ASDs and performing virtual bioequivalence evaluation of these generic drug products.


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 = $249,485 )
2025	2025	SIMULATIONS PLUS INC	800 PARK OFFICES DR STE 401	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Food and Drug Administration Research	000	2	8/27/2025	NON-COMPETING CONTINUATION	$249,485
														Subtotal = $249,485

Issue Date FY: 2024 ( Subtotal = $249,485 )
2024	2024	SIMULATIONS PLUS INC	42505 10TH ST W STE 103	LANCASTER	CA	93534	LOS ANGELES	USA	Food and Drug Administration Research	000	1	9/2/2024	NEW	$249,485
														Subtotal = $249,485

Grand Total All Awards = $498,970

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From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions

Award Number: U01FD008388

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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