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Physiologically Based Pharmacokinetics in Critically Ill Children on Dialysis

Award Number: K23HD118284
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/08/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Physiologically Based Pharmacokinetics in Critically Ill Children on Dialysis - PROJECT SUMMARY Over 200,000 children are admitted to a pediatric intensive care unit (PICU) annually in the United States.1 Of those admitted to the PICU, approximately 40% present with acute kidney injury (AKI).2 Sepsis is a leading cause of AKI in PICU patients, and need for dialysis is independently associated with increased mortality in this population (OR 9.7, p = 0.0049).3 The high mortality is suspected to be, in part, a result of suboptimal drug exposure due to significantly altered antimicrobial disposition by the continuous renal replacement therapy (CRRT) circuit.4,5 The majority of drugs prescribed to children on CRRT lack dosing information specific to this population.7 Dosing is different in this population because CRRT can alter drug pharmacokinetics (PK). The PK of drugs in children on CRRT can be altered by 1) drug adsorption by components of the CRRT circuit; 2) drug clearance by the circuit (hemofiltration); and 3) physiologic alterations due to the circuit and underlying critical illness. There are three limitations to PK trials in children on CRRT: 1) The effect of CRRT on drug exposure varies by drug, necessitating a trial for each drug of interest8; 2) PK is known to vary with age9-11; 3) and CRRT technology changes over time, and with it, the impact on drug disposition.12-14 Enrolling the number of children required with traditional trial designs to characterize the PK 1) across the pediatric age spectrum, 2) for every drug used in in CRRT, 3) for each of the different circuit manufacturers, and 4) to repeat the trials anytime a new device is developed, is essentially impossible. Our team developed an alternative approach that addresses these limitations by using physiologically based pharmacokinetic (PBPK) models to translate results from benchside CRRT experiments into bedside dosing recommendations. The objective of this proposal is to determine optimal dosing of commonly used antimicrobials in adapted adult CRRT machines (PrisMax) and purpose-built infant CRRT machines (CARPEDIEM). In AIM 1 we will quantify the impact of CRRT on the disposition of two antimicrobials in ex vivo adapted adult and purpose-built infant CRRT systems. AIM 2 will use these ex vivo data to parameterize a CRRT compartment and develop PBPK models to predict optimal CRRT dosing for each drug. The models for each drug will utilize a common infant PBPK structure integrated with a machine-specific CRRT compartment. In AIM 3, the models will be qualified with prospectively collected concentration data from infants supported with adapted adult and purpose-built infant CRRT circuits. This approach will formally access our ability to utilize circuit-specific ex vivo data to update qualified PBPK models. Following full model qualification using traditional metrics, we will also calculate normalized prediction distribution errors to quantify the minimum number of participants needed to qualify these new models, gaining efficiency in future studies. The results of this study will improve the safety and effectiveness of these commonly used antimicrobials in critically ill infants on CRRT and provide a validated platform for rapid determination of drug dosing in future R-level proposals.


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: 2026 ( Subtotal = $699,840 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/8/2026	NEW	$699,840
														Subtotal = $699,840

Grand Total All Awards = $699,840

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Physiologically Based Pharmacokinetics in Critically Ill Children on Dialysis

Award Number: K23HD118284

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/08/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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