387 - Physiologically Based Pharmacokinetic Modeling of Intravenous Anakinra Exposure in Children

Publication Number: 3374.387

Danielle J. Green, University of Utah School of Medicine, Salt Lake City, UT, United States; Samuel Dubinsky, Dalhousie University Faculty of Medicine, Halifax, NS, Canada; Autumn McKnite, University of Utah School of Medicine, Salt Lake City, UT, United States; Mark Hall, Nationwide Children's Hospital, Columbus, OH, United States

Background: Anakinra is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist that competitively inhibits IL-1 binding. In children, it is approved for rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, and it is increasingly used off-label for other hyperinflammatory syndromes. Despite its expanding use, pediatric dosing remains largely extrapolated from adults without a mechanistic understanding of age-dependent pharmacokinetics (PK). Physiologically based pharmacokinetic (PBPK) modeling provides a framework to predict pediatric exposure by integrating developmental physiology with drug-specific parameters.

Objective: To develop a pediatric PBPK model of intravenous (IV) anakinra and characterize age-dependent differences in exposure.

Design/Methods: A previously validated adult IV anakinra PBPK model (Dubinsky et al., Clin Pharmacokinet 2024) was scaled to pediatrics in PK-Sim® using age-dependent physiological parameters. Clearance was represented as the sum of glomerular filtration and proteolysis. Glomerular filtration rate (GFR) was scaled to children to account for ontogeny, while the proteolysis rate was retained from the adult model. Model predictions were evaluated against observed plasma concentration–time data in children with acute Kawasaki disease (Yang et al., J Pediatr 2022). Model performance was assessed using average fold error (AFE) and absolute average fold error (AAFE).

Results: Model predictions were within 2.5-fold of observed data (AFE = 0.7; AAFE = 2.42), consistent with acceptable predictive performance for a scaled pediatric model.

Conclusion(s): The pediatric IV anakinra PBPK model reasonably reproduces observed plasma concentrations and captures age-dependent clearance differences. Next steps include incorporating critical-illness–related physiologic alterations and validating the model in children with sepsis-induced multiple organ dysfunction syndrome.

Figure 1. Pediatric anakinra IV model simulation.
Observed data reported as mean (circles) with standard deviation (error bars) from individuals in the study conducted by Yang et al (J Pediatr 2022). The solid line represents the simulated plasma concentrations of anakinra IV 4.5 mg/kg in a virtual individual representing the median demographics of study participants.