Population pharmacokinetic analysis of levetiracetam therapeutic drug monitoring data of preterm newborns with neonatal seizures

Neonatal seizures remain a significant neurologic condition with higher incidences in preterm newborns. There still is a lack of evidence-based recommendations for the optimal choice of antiseizure drug (ASD) and effective dosing in term and preterm neonates. Phenobarbital continues to be widely used as the first-line ASD in neonates. Levetiracetam (LEV) is a relatively new ASD with favorable safety profile and positive efficacy outcomes for neonatal seizures. LEV is increasingly being used to treat seizures in newborns. Objective of the research: the population PK modeling based on TDM data assessed at intravenous (IV) LEV monotherapy as the first-line ASD in preterm newborns. Materials and methods: of 45 preterm neonates included in the LEV retrospective PK analysis, gestational age (GA) ranged from 22 to 36 weeks, in 30 (67%) patients GA was 22-28 weeks. Population and individual PK parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough TDM. Samples were assayed by high-performance liquid chromatography. One-compartment PK model with zero-order input and first-order elimination was used to fit LEV concentration data from 101 TDM occasions (201 measured concentrations totally). In the majority of cases, the LEV daily doses were 30 mg/kg/day (ranged from 20 up to 50 mg/kg/day), administered twice a day with 12-hour dosing interval in divided doses. Univariate and multivariate regression analysis was used to evaluate the influence of patient’s covariates on distribution of the estimated LEV PK parameters. Results: when compared to adults and older children, preterm newborns were found to have in average a higher volume of distribution (V), longer half-life (T1/2) and lower clearance (CL). Taking into consideration the lower GA and PCA of the neonates included into this PK study, the identified population PK parameters of LEV in preterm newborns were in good agreement with those published in the literature for neonates: the estimated T1/2 values have a 20% to 80% range of 11 to 32 hrs, the median values for CL and V were 1,22 ml/min/kg and 1,5 L/kg, respectively. LEV was tolerated well in the study age-group, no serious adverse events were evident during or after 30-min IV LEV infusions. Conclusion: the study revealed significant variability in the estimated PK parameters in preterm infants. The results of regression analysis showed that it is not possible to fully explain PK variability using covariates in a statistical model. Personalizing of the LEV anti-seizure treatment for the preterm newborns can be based on the Bayesian forecasting approach and a patient’s TDM data. © 2021, Pediatria Ltd.. All rights reserved.