PII-160 - AGE-APPROPRIATE DOSING FOR DEXAMETHASONE TO PREVENT POST-EXTUBATION STRIDOR: A PEDIATRIC PBPK MODELING APPROACH

J. Van der Heijden¹, N. Hoevenaars¹, M. de Hoop-Sommen¹, J. Freriksen¹, K. Joosten², R. Greupink¹, S. de wildt^1,2; ¹Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud university medical center -, Nijmegen, The Netherlands, ²Department of Neonatal and Pediatric Intensive Care, Division of Pediatric Intensive care, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Age-related physiological changes can significantly impact pharmacokinetics (PK). These alterations necessitate age-appropriate dosing to ensure optimal drug efficacy and safety. Age-appropriate dosing recommendations can be developed with physiologically-based pharmacokinetic (PBPK) modeling, omitting the necessity to conduct additional clinical trials. Dexamethasone, a CYP3A4 metabolized drug, is prescribed intravenously (IV) in the pediatric and neonatal intensive care unit to prevent post-extubation stridor (PES). Its current dosing recommendation does not seem to fully account for CYP3A4 ontogeny and, therefore, we aimed to optimize dexamethasone dosing in children with PBPK modeling.

Methods: A dexamethasone PBPK model was employed in Simcyp™ v21 to predict PK in children. We used the Upreti CYP3A4 profile and model predictions were compared to pediatric PK data. After verifying model performance, alternative dosing regimens were simulated to explore the most optimal doses for dexamethasone per age group. No clear therapeutic window has been defined for dexamethasone and the evidence of efficacy is strongest in the 2-6 years age group. We then used exposures resulting from the effective doses from this age group for all other age groups as well.

Results: Dexamethasone plasma concentrations upon single and multiple IV administration were predicted very accurately across the pediatric age range. After model verification, exposure-matched predictions of dexamethasone indicated that no dosing adjustments were required for the ages between 3 months and 2 years compared to the 2-6 years age group. The dose should be reduced with 20% for the age groups 1-3 months and 6-12 years in order to obtain similar total exposures. For the age groups 2-4 weeks and 12-18 years this was a 40% reduction, while for the 0-2 weeks age group a reduction of 60% was necessary.

Conclusion: We propose PBPK model-informed age-appropriate dosing recommendations for IV dexamethasone to prevent PES in children. Our data indicate that, based on exposure matching, the dose of dexamethasone should be lowered compared to the current dosing guidelines in certain age groups.