ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Obstetric and Pediatric Pharmacology
Physiologically-based pharmacokinetic modeling and simulation for initial dose optimization of levetiracetam in pediatrics
Provisionally accepted
Julia Macente1
Rodolfo Hernandes Bonan2Edilainy Caleffi-Marchesini3
Leonardo Régis Leira Pereira4Priscila de Freitas Lima5
Pieter Annaert2,6
Karel Allegaert6,7*
Andrea Diniz3*- 1KU Leuven, Leuven, Belgium
- 2BioNotus GCV, Niel, Belgium
- 3Universidade Estadual de Maringa, Maringá, Brazil
- 4Universidade de Sao Paulo Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Ribeirao Preto, Brazil
- 5Centro Universitario Barao de Maua, Ribeirao Preto, Brazil
- 6Katholieke Universiteit Leuven, Leuven, Belgium
- 7Erasmus MC, Rotterdam, Netherlands
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Introduction: Optimizing levetiracetam (LEV) dosing in children is challenging due to high pharmacokinetic variability, which often necessitates empirical dose titration. This study aimed to develop and verify a physiologically-based pharmacokinetic (PBPK) modeling and simulation to guide and optimize initial LEV dose selection in pediatric patients. Methods: A whole-body PBPK model for LEV was developed and verified in adults, then scaled and verified in a pediatric population (0.5–12 years). This model was used to simulate various dosing regimens. Subsequently, a multivariate linear regression (MLR) analysis correlated key covariates (dose, regimen, body weight, and glomerular filtration rate) with simulated steady-state peak (Cmax) and trough (Ctr) concentrations to create a practical dosing tool. Results: The MLR model successfully explained over 90% of the variance (R² > 0.9) between covariates and simulated plasma concentrations. For a twice-daily regimen, daily doses of 40–60 mg/kg were required to achieve concentrations within a target therapeutic window (e.g., Cmax of 20–46 mg/L). A three-times-daily regimen allowed for a broader effective dose range of 50–80 mg/kg/day, enabling higher total daily doses while maintaining Cmax within a safe range. Conclusion: The combined PBPK-MLR approach provides a robust, data-driven framework to support rational first-dose prescriptions of LEV in children. his tool has the potential to accelerate therapeutic effects while enhancing treatment individualization. Prospective clinical validation is required to confirm the model predictive performance for drug exposure and, consequently, its impact on therapeutic efficacy.
Keywords: levetiracetam, PBPK modeling, Pediatric Population, Dose optimization, Epilepsy
Received: 03 Aug 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Macente, Hernandes Bonan, Caleffi-Marchesini, Pereira, de Freitas Lima, Annaert, Allegaert and Diniz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Karel Allegaert, allegaertkarel@hotmail.com
Andrea Diniz, adiniz@uem.br
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.