Dados do Trabalho

Título

Is the Physiologically-based Pharmacokinetic modeling able to help in deciding the initial prescription of levetiracetam for the pediatric population?

Introdução

The physiologic-based pharmacokinetic (PBPK) modeling is the newest approach of modeling and simulation (M&S) and has been applied on model-informed precision dosing (MIPD).

Objetivo

This aim was to develop a model to support the dose optimization of levetiracetam in the pediatric population.

Método

A PBPK model of levetiracetam (LEV) was developed for children (0.5 to 12 years old) in Gastroplus Software (Simulation Plus). Predictions of LEV exposure at steady-state were carried out for different therapeutic regimens to achieve the target of Cmax values (20 to 46 µg ml-1) (1). Then, a multivariate linear regression analysis (MLR) was used to build an equation to estimate initial dose for pediatrics.

Resultados

The results indicated that for twice a day (BID) regimen the daily dose able to reach the therapeutic window was between 40 to 60 mg kg-1 for children 0.5 to 12 y.o. For three times a day (TID) regimen, the range of daily dose (DD) considered safe was 50-80 mg kg-1 for 0.5 to 12 y.o. The relationship between Cmax and covariates to build a mathematical model for clinical calculation of the first dose for children was: Cmax.=11.92+(0.50∙Dose)+(0.28∙WT)-(7.82∙Reg)-(5.51∙GFR), where where Cmax is given as mg L-1; dose is given as mg kg-1 day-1, WT is weight in kg, and Reg is the Regimen as 1 for BID and 2 for TID and GFR is the glomerular filtration rate in mL sec-1. Clinical studies published previously showed that high doses (90 to 120 mg kg-1) were administrated for pediatric patients age of 2 y.o had received these doses after intravenous administration (2), and older pediatrics (mean age 11 y.o), orally (3). The effectiveness in reducing the frequency of seizure crisis and safety was demonstrated for both studies. Another case report showed a 7 y.o. child which had taken 200 mg kg-1 per day for 55 days and no adverse effects were reported, suggesting a possible safety evidence for increasing the maximum dose recommended (4).

Conclusão

The MIPD could be supportive for clinical decisions for the first prescription of levetiracetam for children from 0.5 years old, until older ages in which the weight is bellow 50 kg, where the regular adult doses need to be assumed.

Financial Support: Capes – Brazil and Araucária Foundation (SETI/Paraná State) (061/2021 - SUS2020131000109).

Palavras-chave

PBPK model; in-vivo predictions; modeling; simulation; levetiracetam