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Anakinra Dosing in Children with Sepsis Induced MODS: A Physiologically Based Pharmacokinetic-Pharmacodynamic Approach

Award Number: K23HD115855
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/05/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Anakinra Dosing in Children with Sepsis Induced MODS: A Physiologically Based Pharmacokinetic-Pharmacodynamic Approach - PROJECT ABSTRACT Treatment of children with sepsis-induced multiple organ dysfunction syndrome (MODS) requires optimal dosing of drugs. Drug dosing may need to be adjusted in these children because of altered drug pharmacokinetics (PK) and pharmacodynamics (PD), resulting from: 1) inflammation and capillary leak leading to increased volume of distribution; and 2) organ dysfunction causing decreased drug clearance. The impact of these alterations can be quantified using physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling. Anakinra is an interleukin-1 receptor antagonist (IL-1Ra) that is FDA approved to treat hyperinflammatory syndromes in children. The use of anakinra in children with sepsis-induced MODS is currently being evaluated in the Personalized Immunomodulation in Pediatric Sepsis-Induced MODS (PRECISE) trial, a multi-center randomized control trial wherein children are randomized to receive anakinra or placebo if they have sepsis-induced MODS with hyperinflammation. In this population, optimal dosing of anakinra is unknown. In addition, the role and kinetics of endogenous IL-1Ra is unknown. These gaps in the understanding of anakinra PK and PD place these children at risk for treatment failure and toxicity. The objective of this proposal is to leverage the PRECISE trial to evaluate the impact of sepsis-induced MODS on the kinetics of endogenous IL-1Ra and anakinra. Based on these results, we will use a PBPK-PD modeling approach to determine a safe and efficacious anakinra dosing regimen. Specifically, the proposed work will 1) characterize the kinetics of endogenous IL-1Ra in children with sepsis-induced MODS who receive placebo in the PRECISE trial; 2) incorporate relevant drug and population specific factors into a PBPK-PD model to predict anakinra disposition and efficacy; 3) validate the model using prospective data obtained from children receiving anakinra in the PRECISE trial and establish a model- and biomarker-informed anakinra dosing regimen. Training will take place at the University of Utah under the mentorship of a pediatric trialist and leading expert in PBPK modeling. Through my training plan, I will develop the necessary skills for a career as an independent physician scientist including training in advanced pharmacology, clinical trial design, scientific communication, and sophisticated modeling and simulation techniques.


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 = $167,400 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	2	8/20/2026	NON-COMPETING CONTINUATION	$167,400
														Subtotal = $167,400

Issue Date FY: 2025 ( Subtotal = $167,400 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	1	9/5/2025	NEW	$167,400
														Subtotal = $167,400

Grand Total All Awards = $334,800

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Anakinra Dosing in Children with Sepsis Induced MODS: A Physiologically Based Pharmacokinetic-Pharmacodynamic Approach

Award Number: K23HD115855

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/05/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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