LB-010 - PEDIATRIC POPULATION PHARMACOKINETIC MODEL DEVELOPMENT FOR ORAL AMOXICILLIN AND CLAVULANIC: LEVERAGING LITERATURE DATA FOR MODEL-INFORMED DRUG EXPOSURE ANALYSIS IN YOUNG CHILDREN.

K. Fukushima¹, T. Mizuno², S. Tang Girdwood², K. Dewedoff, C. Peck, A. Vinks²; ¹Kobe Gakuin University, Kobe, Japan, ²Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.

Background: Amoxicillin (Amo) with clavulanic acid (Clav) is currently the most effective antimicrobial in treating children with recurrent acute otitis media (AOM) or AOM caused by gram negative bacteria. In young children with AOM, a Clav dose lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. However, the optimal Clav exposure remains unclear in children with AOM. In this study, we developed pediatric PK models for oral Amo/Clav using literature data to evaluate drug exposure in young children compared to older children and adults.

Methods: Adult PK models for Amo/Clav were used as base models [1,2]. The base pediatric models included allometric body weight and maturation functions to account for body size and developmental changes. The absorption parameters were then optimized using pediatric PK data available from the GSK Clinical Studies Register (ID: 25000/574)[3]. The final models were externally qualified using pediatric data from 10 PK studies.

Results: The Amo/Clav mean predicted Cmax with the base pediatric model were higher than the published data. After model optimization, the oral bioavailability was estimated to be 76% and 64% lower than observed in adults for Amo and Clav, respectively. External qualification showed that the mean dose-normalized AUCs predicted with the final model were within the 95% prediction intervals for ８ out of 10 studies. The 2 studies outside of the 95% prediction intervals included small sample size (n≤4).

Conclusion: This study generated the first pediatric PK models for oral Amo/Clav. The final models will be used for model-informed clinical trial design optimization and exposure analysis of Amo/Clav in young children.

1. De Velde F, de Winter BC, Koch BC, van Gelder T, Mouton JW; COMBACTE-NET consortium. Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints. J Antimicrob Chemother. 2016 Oct;71(10):2909-17.
2. De Velde F, De Winter BCM, Koch BCP, Van Gelder T, Mouton JW; COMBACTE-NET consortium. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J Antimicrob Chemother. 2018 Feb 1;73(2):469-476.
3. GSK Clinical Studies Register website (https://www.gsk-studyregister.com/en/trial-details/?id=25000/574). Accessed 8 November 2022.