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Formulation toolbox for topically applied drugs to account for physical parameters, dynamic metamorphosis and influence of excipients

Award Number: U01FD007954
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Formulation toolbox for topically applied drugs to account for physical parameters, dynamic metamorphosis and influence of excipients - Project Summary/ Abstract Physiologically-based pharmacokinetic (PBPK) modelling has emerged as a valuable tool in the drug development process for both novel and generic drug products. In particular, simulation tools can be utilised for generic drug products to assess virtual bioequivalence between the reference and test products. Dermal PBPK modelling has been applied to the development of topical formulations by predicting drug absorption into skin in virtual populations that are constructed using realistic physiology data. It is important to recognise that topical products undergo changes immediately upon application due to formulation metamorphosis, which may alter the critical characteristics of the formulations. To accurately simulate drug permeation through the skin, precise parameterisation of the dynamic changes that occur during formulation metamorphosis is crucial. A primary objective of this grant proposal is to improve the formulation parameterisation integrated in the MPML MechDermA model by integrating dynamic formulation compositions and feedback to critical quality attributes using advanced prediction methods. The other primary objective is to systematically verify the model’s predictive capability by assessing its ability to account for variations in drug product attributes and to predict the influence of these variations on the local bioavailability. Specifically, Aim 1 will focus on the enhancement of the formulation toolbox by enabling the input of complete formulation composition data (Q2) and implementing predictive methods to estimate formulation Q3 properties based on known Q2 characterisation. The proposed framework will be used in pursuit of Aim 2, wherein individual volatile constituents will be allowed to evaporate and dynamic re-calculation of formulation Q2 and Q3 metrics implemented. In addition to evaporation, the depletion of excipient through skin absorption will be investigated under Aim 3. Commercial and custom desoximetasone drug products featuring modified formulation attributes will be designed and characterised under Aim 4. These formulations will serve as challenges for the PBPK models, which will be used to verify the models’ ability to differentiate between formulation variations and assess bio(in)equivalence. Aim 5 will focus on the evaluation of skin hydration following formulation application involving the development and validation of a PBPK model of skin hydration and absorption of water from topical drug products. Aim 6 will develop a model for simulating microdialysis and open-flow microperfusion data; this model will be leveraged to simulate available data on local concentrations in vivo and further verify local concentration predictions.


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: 2024 ( Subtotal = $249,922 )
2024	2024	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	002	2	8/28/2024	NON-COMPETING CONTINUATION	$249,922
2024	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	000	1	2/26/2024	NEW	-$249,996
2024	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	001	1	3/8/2024	NEW	$249,996
														Subtotal = $249,922

Issue Date FY: 2023 ( Subtotal = $249,996 )
2023	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	003	1	9/28/2023	NEW	$249,996
2023	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	000	1	8/16/2023	NEW	$249,996
2023	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	002	1	9/27/2023	NEW	-$249,996
2023	2023	CERTARA UK LIMITED	LEVEL 2-ACERO - 1 CONCOURSE WAY - SOUTH YORKSHIRE	SHEFFIELD				GBR	Food and Drug Administration Research	001	1	9/25/2023	NEW	$0
														Subtotal = $249,996

Grand Total All Awards = $499,918

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Formulation toolbox for topically applied drugs to account for physical parameters, dynamic metamorphosis and influence of excipients

Award Number: U01FD007954

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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