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Biodistribution and PK modeling of rat vs. human systems

Award Number: R44ES032360
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Biodistribution and PK modeling of rat vs. human systems - Project Summary/Abstract We propose to construct multi organ microphysiological systems (“Body-on-a-Chip” or BoaCs) from human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals in a system to evaluate biodistribution. A GI tract/BBB/neuronal BoaC will be constructed in Phase I and liver added in Phase II. This work will directly test whether such in vitro models can accurately reproduce species differences in response to known drugs. A preclinical model based on human cells that can accurately predict human response should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humans. Also, the tissues can exchange metabolites and the dose dynamics in the body of both parental compounds and metabolites are better represented than when a single cell type is exposed to a bolus dose. In addition, by comparing acute to chronic effects it will enable prediction on clinical trial success as well for determining PK of the compounds. In addition, the comparison of animal cells derived from iPSCs will enable the assessment of whether they can be substituted for primary animal cells. If successful, this could lead to stable cell sources for the animal models and reduce the number of animals needed for these studies. Changes in LTP will be utilized as it is a functional measurement of neuronal activity known to correlate with changes in memory and learning. The integration of this neuronal module with a human-on-a-chip system that includes a blood-brain-barrier (BBB) and GI tract. Inclusion of the liver in Phase II also allows investigation of the effect of metabolites in addition to the parent compound. To construct a well defined system we will use a common serum free medium which mimics key features of blood. Hickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts for not only acute but also chronic tests as well. To improve operability and enable a low volume system for eventual metabolite evaluation, we will use a pumpless system (Sung, et al. 210) and self contained devices. We will also utilize microfluidic analytical components for rapid and sensitive biomarker assessment. The system will be modeled by simulation using CFD to establish acceptable ranges for consumption of nutrients and drug metabolism as well as shear stress and to predict drug concentration profiles in the system. We also will partner with Dr. Stephan Schmidt, an expert in drug-disease modeling and simulation approaches, to develop pharmacokinetic/pharmacodynamic (PBPK/PD) models to relate the in vitro studies to clinical outcomes. We believe that this technique will lead to more accurate and cost-effective assessment of the efficacy and toxicological potential of drugs chemicals or chemical mixtures and this approach will have a major impact on improving human health. Further, the combination of a multi-organ in vitro model with PBPK/PD modeling offers an opportunity to integrate direct experimental observations with a physiologically realistic mathematical model which will facilitate extrapolation of in vitro data to improved prediction of human response.


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	2022	HESPEROS, INC	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	000	3	6/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	HESPEROS, INC	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	000	3	3/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $789,413 )
2022	2022	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	000	3	2/24/2022	NON-COMPETING CONTINUATION	$754,240
2022	2022	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	001	3	4/13/2022	NON-COMPETING CONTINUATION	$35,173
														Subtotal = $789,413

Issue Date FY: 2021 ( Subtotal = $764,240 )
2021	2021	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	001	2	2/24/2021	EXTENSION WITH OR WITHOUT FUNDS	$754,240
2021	2020	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	002	1	8/13/2021	NEW	$0
2021	2020	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	000	1	10/28/2020	NEW	$10,000
														Subtotal = $764,240

Issue Date FY: 2020 ( Subtotal = $216,260 )
2020	2020	HESPEROS, INC.	12501 RESEARCH PKWY STE 100	ORLANDO	FL	32826	ORANGE	USA	Environmental Health	000	1	9/10/2020	NEW	$216,260
														Subtotal = $216,260

Grand Total All Awards = $1,769,913

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Biodistribution and PK modeling of rat vs. human systems

Award Number: R44ES032360

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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