Journal Article

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

Wang, Sonya, Rasmussen, Maynard, Rismanchi, Neggy, Kim, Jae, Harbert, Mary Jo, Honold, Jose, Yang, Derek Z, Battin, Malcolm R., Kuperman, Rachel, Sharpe, Cynthia, Capparelli, Edmund V, Lane, Brian, Nespeca, Mark, Gold, Jeffrey J., Ernstrom, Karin, Haas, Richard H, Michelson, David, Reiner, Gail E, Knodel, Ellen, Arnell, Kathy, Joe, Priscilla, Lee, Lilly, Davis, Suzanne L., Raman, Rema, diagnostics, Quest, Mower, Andrew, Bridge, Renee

2024

Overview

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic 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.SettingNeonatal intensive care unit.PatientsTerm neonates with electrographically confirmed seizures.InterventionsIn 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 measuresClearance (CL) and volume of distribution (Vd) were determined. Covariates that significantly affected LEV disposition were identified.ResultsPrimary 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%.ConclusionsLEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.Trial registration number NCT01720667.

• Publisher: BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health,BMJ Publishing Group LTD
• Subject: Anesthesia / Anticonvulsants - administration & dosage / Anticonvulsants - pharmacokinetics / Anticonvulsants - therapeutic use / Child Health / Children & youth / Clinical trials / Dose-Response Relationship, Drug / Drug dosages / Drug therapy / Effect Size / Electroencephalography - drug effects / Ethics / Etiracetam / Female / Humans / Infant, Newborn / Intensive care / Intensive Care Units, Neonatal / Intravenous administration / Language Maintenance / Levetiracetam - administration & dosage / Levetiracetam - pharmacokinetics / Levetiracetam - therapeutic use / Maintenance / Male / Neonatal care / Neonates / Neonatology / Neurology / Outcome Measures / Paediatrics / Patients / Pediatrics / Pharmacodynamics / Pharmacokinetics / Pharmacology / Phenobarbital / Phenobarbital - administration & dosage / Phenobarbital - pharmacokinetics / Phenobarbital - therapeutic use / Piracetam - administration & dosage / Piracetam - analogs & derivatives / Piracetam - pharmacokinetics / Proteins / Seizures / Seizures - drug therapy / Standard of care / Statistical Significance / Treatment Outcome