Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population
Document Type
Article
Publication Date
6-1-2024
Identifier/URL
41552895 (Pure); 38814425 (PubMed); PMC11225543 (PubMedCentral)
Abstract
Background: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. Objective: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework. Methods: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models. Results: Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature. Conclusions: PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.
Repository Citation
Maglalang, P. D.,
Sinha, J.,
Zimmerman, K.,
McCann, S.,
Edginton, A.,
Hornik, C. P.,
Hornik, C. D.,
Muller, W. J.,
Al-Uzri, A.,
Meyer, M.,
Chen, J. Y.,
Anand, R.,
Perrin, E. M.,
Gonzalez, D.,
Delmore, P.,
Dixit, S.,
Shimizu, J.,
Shakespear, K.,
Salman, Y.,
Rosen, P.,
Perez, R.,
Narus, J. A.,
Alger, F.,
Sherwin, C.,
Spigarelli, M.,
Talbert, J.,
Mariconti, A.,
Bernhardt, J.,
Laughon, M.,
Wiseheart, M.,
& Perry, J.
(2024). Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population. Clinical Pharmacokinetics, 63 (6), 885-899.
https://corescholar.libraries.wright.edu/pediatrics/775
DOI
10.1007/s40262-024-01367-2
Comments
Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.