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Integration of Drug Release and Permeability with Systems Data Relevant to PBPK Model of Nose-to-Brain Axis and Verification Using Clinical Data

Award Number: U01FD007657
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Integration of Drug Release and Permeability with Systems Data Relevant to PBPK Model of Nose-to-Brain Axis and Verification Using Clinical Data - Project Summary Intranasal (IN) drug delivery is an attractive route as it avoids the hepatic first-pass effect and has a rapid-onset of action due to direct access to central nervous system (CNS). It has been suggested as a route to achieve effective drug concentration for treatment of neurological disorders where drug distribution to the CNS following delivery by other routes may be challenging due to the presence of blood-brain-barrier (BBB) and/or efflux transporters that reduce drug CNS exposure. Office of Generic Drugs (OGD) has prioritised access to generic drugs to ensure safe and effective use in patients. The importance of generic drugs has also been recognised by the FDA through the Generic Drug User Fee Amendments (GDUFA). Mechanistic tools such as physiologically-based pharmacokinetic (PBPK) models will further ensure development of quality, safe and effective generic drugs for delivery by IN route. Currently, there is no PBPK model in the literature that adequately accounts for important components such as direct nose-to-brain pathway, the role of transporters in the CNS drug disposition, the role of complex absorption process and the interplay between all these dynamic processes. In this project PBPK models for drugs delivered by IN route will be developed, linking the nose-to-brain pathway to the disposition of drug within the CNS and the rest of the body. This approach is based on in vitro-in vivo extrapolation (IVIVE) principles and builds on our current project on development of IVIVE-PBPK models for CNS drug disposition to link cerebrospinal fluid to localized brain concentration for compounds with mild-to- moderate efflux liabilities. In our proposal we will focus on three drugs: zolmitriptan, naloxone and oxycodone. Literature in vitro and clinical data will be used for initial model development; however, gaps will be filled with experimental data generated within this project. Proteomics data from olfactory region of human tissue will be generated and implemented in the model to account for the role of transporters in drug uptake. A prospective dedicated clinical trial following intravenous and IN delivery of three selected drugs will be used as an independent dataset for model validation and qualification. These data are critical for PBPK-driven deconvolution which is necessary to account for entry rate of the drugs following intranasal delivery, which will also be useful to explore complex interplay between permeability and transporter kinetics. All our methods and codes will be published for open access by PBPK users and commercial platform developers to create an immediate path for practical application by pharmaceutical scientists.


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	THE UNIVERSITY OF MANCHESTER	OXFORD ROAD	MANCHESTER				GBR	Food and Drug Administration Research	000	2	9/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE UNIVERSITY OF MANCHESTER	OXFORD ROAD	MANCHESTER				GBR	Food and Drug Administration Research	000	2	9/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $264,446 )
2023	2023	THE UNIVERSITY OF MANCHESTER	OXFORD ROAD	MANCHESTER				GBR	Food and Drug Administration Research	000	2	8/2/2023	NON-COMPETING CONTINUATION	$264,446
														Subtotal = $264,446

Issue Date FY: 2022 ( Subtotal = $297,306 )
2022	2022	UNIVERSITY OF MANCHESTER	OXFORD RD	MANCHESTER	LANCASHIRE			GBR	Food and Drug Administration Research	000	1	9/9/2022	NEW	$297,306
														Subtotal = $297,306

Grand Total All Awards = $561,752

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Integration of Drug Release and Permeability with Systems Data Relevant to PBPK Model of Nose-to-Brain Axis and Verification Using Clinical Data

Award Number: U01FD007657

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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