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Design, Development, Implementation and Validation of a Mechanistic Physiologically-based Pharmacokinetic (PBPK) Framework for the Prediction of the In Vivo Behaviour of Supersaturating Drug Products

Award Number: U01FD005865
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary / Abstract Physiologically-based pharmacokinetic (PBPK) models can separate drug/formulation characteristics from the underlying physiology and are well positioned to predict PK including inter-individual variability. A further advantage of Population PBPK is the ability to extrapolate from a model validated for a particular drug/formulation in one population (e.g., healthy volunteer) to another population (e.g., elderly or paediatric) provided the physiological differences are sufficiently well characterised. The Simcyp Population-Based Simulator includes a sophisticated oral absorption module which can simulate clinical trials predicting inter-individual variability rather than just an ‘average person’. This project aims to incorporate state-of-the art mechanistic models for handling supersaturation and precipitation (S&P) properties of poorly soluble drug products. S&P properties can have a major influence on the overall bioavailability of such compounds. Thus, the ability to anticipate these properties from in vitro experiments and extrapolate to in vivo outcomes can be critical to a drug development program; where appropriate formulation strategies can be followed to either prevent precipitation or mitigate its impact. The PBPK models require: drug and formulation-specific information; mechanistic algorithms for not only precipitation itself (such as, but not only, classical nucleation theory) but also the numerous other processes occurring within the gastrointestinal tract and the associated physiological and anatomical parameters and their inter-individual variability, which play an important role in supersaturation/precipitation behaviour in vivo. This includes gastric and small intestinal luminal fluid volumes; gastrointestinal transit times of fluids, fine particles and intact single unit dosage forms; regional luminal pH; fluid viscosity, effect of excipients, etc. The new mechanistic models are to be incorporated into both the Simcyp platform itself and crucially into separate complementary tools for modelling appropriate in vitro experiments such as media transfer experiments. This parallel implementation is essential for understanding, testing and parameterising the models. The existing standalone Simcyp In Vitro Analysis (SIVA) toolkit provides an ideal framework within which to add new modelling algorithms. At least eleven model drug products dosed under various conditions and exemplifying different mechanisms of supersaturation and precipitation are considered to be used for performance verification of the developed models and physiologies the results of which will be disseminated to the general scientific community through appropriate channels.


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: 2021 ( Subtotal = $0 )
2021	2017	CERTARA UK LIMITED	LEVEL 2-ACERO, 1 CONCOURSE WAY,	SHEFFIELD	SOUTH YORKSHIRE			GBR	Food and Drug Administration Research	000	2	2/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	CERTARA UK LIMITED	LEVEL 2-ACERO, 1 CONCOURSE WAY,	SHEFFIELD	SOUTH YORKSHIRE	S1 2BJ		GBR	Food and Drug Administration Research	000	2	4/10/2019	NON-COMPETING CONTINUATION	$0
2019	2017	CERTARA UK LIMITED	LEVEL 2-ACERO, 1 CONCOURSE WAY,	SHEFFIELD	SOUTH YORKSHIRE	S1 2BJ		GBR	Food and Drug Administration Research	001	2	6/25/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	CERTARA UK LIMITED	LEVEL 2-ACERO, 1 CONCOURSE WAY,	SHEFFIELD	SOUTH YORKSHIRE	S1 2BJ		GBR	Food and Drug Administration Research	001	2	7/18/2018	NON-COMPETING CONTINUATION	$0
2018	2017	SIMCYP LTD	BLADES ENTERPRISE CENTRE	SHEFFIELD	SOUTH YORKSHIRE	S2 4SU		GBR	Food and Drug Administration Research	000	2	10/25/2017	NON-COMPETING CONTINUATION	$0
2018	2017	CERTARA UK LIMITED	LEVEL 2-ACERO, 1 CONCOURSE WAY,	SHEFFIELD	SOUTH YORKSHIRE	S1 2BJ		GBR	Food and Drug Administration Research	002	2	8/16/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $284,895 )
2017	2017	SIMCYP LTD	BLADES ENTERPRISE CENTRE	SHEFFIELD	SOUTH YORKSHIRE	S2 4SU		GBR	Food and Drug Administration Research	000	2	8/9/2017	NON-COMPETING CONTINUATION	$284,895
														Subtotal = $284,895

Issue Date FY: 2016 ( Subtotal = $248,565 )
2016	2016	Simcyp Ltd	Blades Enterprise Centre	Sheffield				GBR	Food and Drug Administration Research	000	1	9/10/2016	NEW	$248,565
														Subtotal = $248,565

Grand Total All Awards = $533,460

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Design, Development, Implementation and Validation of a Mechanistic Physiologically-based Pharmacokinetic (PBPK) Framework for the Prediction of the In Vivo Behaviour of Supersaturating Drug Products

Award Number: U01FD005865

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: COOPERATIVE AGREEMENT

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

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