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Randomized Controlled Trial
. 2024 Sep 25;109(10):854-860.
doi: 10.1136/archdischild-2022-324952.

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

Cynthia Sharpe  1   2 , Derek Z Yang  3 , Richard H Haas  2   4 , Gail E Reiner  2 , Lilly Lee  2 , Edmund V Capparelli  3 ; NEOLEV2 Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

Cynthia Sharpe et al. Arch Dis Child. .

Abstract

Objectives: To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.

Design: Pharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted.

Setting: Neonatal intensive care unit.

Patients: Term neonates with electrographically confirmed seizures.

Interventions: In NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction.

Main outcome measures: Clearance (CL) and volume of distribution (Vd) were determined. Covariates that significantly affected LEV disposition were identified.

Results: Primary outcome: The median initial LEV level was 57 µg/mL (range 19-107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and Vd were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and Vd were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and Vd (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%.

Conclusions: LEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.

Trial registration number: NCT01720667.

Keywords: Neonatology; Neurology; Paediatrics; Pharmacology.

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Conflict of interest statement

Competing interests: RHH and CS have done consulting work for Sparc pharmaceuticals who are seeking FDA indication for PHB in the treatment of neonatal seizures.

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