Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population.

Autor: Maglalang PD; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Sinha J; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Pediatrics, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Zimmerman K; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.; Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA., McCann S; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Edginton A; School of Pharmacy, University of Waterloo, Waterloo, ON, Canada., Hornik CP; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.; Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA., Hornik CD; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.; Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA., Muller WJ; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA., Al-Uzri A; Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA., Meyer M; Nemours Children's Health, Wilmington, DE, USA., Chen JY; The Emmes Company, LLC, Rockville, MD, USA., Anand R; The Emmes Company, LLC, Rockville, MD, USA., Perrin EM; Department of Pediatrics, School of Medicine and School of Nursing, Johns Hopkins University, Baltimore, MD, USA., Gonzalez D; Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA. daniel.gonzalez@duke.edu.; Division of Clinical Pharmacology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA. daniel.gonzalez@duke.edu.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2024 Jun; Vol. 63 (6), pp. 885-899. Date of Electronic Publication: 2024 May 30.
DOI: 10.1007/s40262-024-01367-2
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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