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Investigation of Drug-Drug and Drug-Circuit Interactions in Children on Continuous Renal Replacement Therapy

Award Number: F31DK130542
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Investigation of Drug-Drug and Drug-Circuit Interactions in Children on Continuous Renal Replacement Therapy - PROJECT SUMMARY/ABSTRACT Continuous renal replacement therapy (CRRT), a form of dialysis, is life saving for children with acute kidney injury. Despite this, children supported with CRRT are at still at high risk for death, with mortality rates exceeding 40%. This high mortality is thought to result in part from altered drug exposure. Altered drug exposure occurs from 1) drug-drug interactions due to the administration of multiple drugs; 2) multi-organ dysfunction; and 3) direct drug interaction and/or removal of drug by the CRRT circuit. As a result, for most drugs, optimal dosing in children on CRRT is unknown. The goal of this study is to determine optimal dosing of 5 commonly used drugs in children on CRRT. In AIM 1 we will determine how drugs interact with the CRRT machines by injecting five drugs singly and together into isolated, closed-loop CRRT circuits. In AIM 2 we will build physiologically based pharmacokinetic (PBPK) models to predict optimal drug dosing in children. PBPK models are computational models in which the body is represented as a set of virtual organ compartments linked by blood flow. Mathematical equations characterize changes in drug concentrations as the drug passes through the virtual organs. These mechanistic models can account for the impact of physiologic covariates such as age and disease and incorporate the impact of drug- drug interactions. Importantly, we can use the data from AIM 1 to build a CRRT “organ” in the PBPK model to account for the impact of CRRT on drug dosing. Finally in AIM 3 we will collect prospective drug concentration data from children who are on CRRT and one or more of the selected drugs. We will compare the observed concentration data from these children with the PBPK model-predicted concentration data in order to refine and validate the PBPK model. We will use the final PBPK model to predict optimal dosing under different scenarios such as drug co-administration and different CRRT settings. This study will determine the PK of common medications and interactions between drugs co-administered in children on CRRT. Results can be directly translated to the bedside and improve safety and effectiveness of drugs used in critically ill children on CRRT. Training will take place at the University of Utah under the mentorship of a leading expert in PBPK modeling. Through my training plan, I will develop the necessary skills for a career as an independent research scientist including the necessary technical skillset, completing coursework in pharmacology/pharmacokinetics, and the effective communication of data and results.


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 = -$5,975 )
2025	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/25/2025	NON-COMPETING CONTINUATION	-$5,975
														Subtotal = -$5,975

Issue Date FY: 2024 ( Subtotal = -$2,262 )
2024	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/21/2024	NON-COMPETING CONTINUATION	-$2,262
														Subtotal = -$2,262

Issue Date FY: 2023 ( Subtotal = $38,726 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/23/2023	NON-COMPETING CONTINUATION	$38,726
														Subtotal = $38,726

Issue Date FY: 2022 ( Subtotal = $37,785 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	7/6/2022	NEW	$0
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/3/2022	NEW	$37,785
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/3/2022	NEW	$0
														Subtotal = $37,785

Grand Total All Awards = $68,274

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Investigation of Drug-Drug and Drug-Circuit Interactions in Children on Continuous Renal Replacement Therapy

Award Number: F31DK130542

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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