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\begin{document}

\title{Model-informed precision dosing of levetiracetam in pediatrics
population}



\author[1]{Julia Macente}%
\author[2]{Frederico Martins}%
\author[1]{Rodolfo Bonan}%
\author[1]{Edilainy Caleffi-Marchesini}%
\author[3]{Leonardo Pereira}%
\author[4]{Priscila Lima}%
\author[5]{Elza Kimura}%
\author[6]{Andrea Diniz}%
\affil[1]{State University of Maringá}%
\affil[2]{University of Sao Paulo Faculty of Pharmaceutical Sciences of Ribeirao Preto}%
\affil[3]{University of Sao Paulo}%
\affil[4]{Barão de Mauá University Centre}%
\affil[5]{Universidade Estadual de Maringá}%
\affil[6]{Universidade Estadual de Maringa Centro de Ciencias da Saude}%


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  \date{May 23, 2024}


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\begin{abstract}
Aims: Assessing the suitability and safety of doses of levetiracetam in
pediatrics using physiologic-based pharmacokinetic (PBPK) modeling.
Methods: A PBPK model of levetiracetam was developed and validated for
healthy adults and scaled for children (0.5 to 12 years old). Prediction
of levetiracetam exposure at steady- state, were carried out for
different therapeutic regimens to achieve the target of Cmax values
within the therapeutic range of 5 to 46 \selectlanguage{greek}µ\selectlanguage{english}g ml-1. Then, a multivariate
linear regression analysis (MLR) was applied to correlate the simulated
data with covariates: dose, therapeutic regimen, sex, age and body
weight (BW), to describe the best model prediction for the initial
dosing in pediatrics. Results: The results indicated the suitability of
the PBPK model for adults and pediatrics. For children aged 0.5 to 6
y.o. the dose range capable of reaching the pharmacokinetic target is
between 10 and 100 mg kg-1 day-1, for 7 to 9 y.o. doses between 20 and
90 mg kg-1 day-1, and for 10 to 12 y.o. doses between 20 to 80 mg kg-1
day-1. Further, the MLR related Cmax to dose, therapeutic regimen, and
BW. Conclusions: For 3 daily administrations, it is suggested that
maximum daily doses of 80 mg kg-1 could be used for ages between 0.5 and
6 y.o. and 100 mg kg-1 for ages above 7 years old, since they weigh
below 50 kg. The PBPK model lumped to MLR could be very supportive for
clinical decisions to safety and effectiveness of prescription of
levetiracetam along the titration phase.%
\end{abstract}%



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