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.