Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population
05/2024
Journal Article
Authors:
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.;
Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering, Committee
Volume:
63
Pagination:
885-899
Issue:
6
Journal:
Clin Pharmacokinet
PMID:
38814425
URL:
https://www.ncbi.nlm.nih.gov/pubmed/38814425
DOI:
10.1007/s40262-024-01367-2
Keywords:
Humans *Levetiracetam/pharmacokinetics/administration & dosage Child, Preschool Child *Models, Biological Infant Adolescent *Anticonvulsants/pharmacokinetics/administration & dosage
Male Female Age Factors Infant, Newborn Young Adult Obesity/metabolism Prospective Studies Computer Simulation
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((R)) 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.
