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Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies
  1. Cynthia Sharpe1,2,
  2. Derek Z Yang3,
  3. Richard H Haas2,4,
  4. Gail E Reiner2,
  5. Lilly Lee2,
  6. Edmund V Capparelli3
  7. NEOLEV2 Investigators
    1. 1Paediatric Neurology, Starship Children's Health, Auckland, New Zealand
    2. 2Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
    3. 3Department of Pediatrics, University of California San Diego, La Jolla, California, USA
    4. 4Department of Neurology, Rady Children's Hospital—San Diego, San Diego, California, USA
    1. Correspondence to Dr Cynthia Sharpe, Paediatric Neurology, Starship Children's Health, Auckland, New Zealand; CynthiaS{at}adhb.govt.nz

    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.

    • Neonatology
    • Neurology
    • Paediatrics
    • Pharmacology

    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • Collaborators NEOLEV2 Investigators: Suzanne L Davis, Mark Nespeca, Jeffrey J Gold, Maynard Rasmussen, Rachel Kuperman, Mary Jo Harbert, David Michelson, Priscilla Joe, Sonya Wang, Neggy Rismanchi, Andrew Mower, Jae Kim, Malcolm R Battin, Brian Lane, Jose Honold, Ellen Knodel, Kathy Arnell, Renee Bridge, Karin Ernstrom, Rema Raman. Quest diagnostics.

    • Contributors CS, RHH and EVC conceptualised the study design. DZY and EVC conceptualised the pharmacodynamic analysis. GER and LL coordinated and acquired the PK data. DZY and EVC performed the data analysis and modelling. All authors were involved in the manuscript drafting and revision process. All authors have approved the final version and are accountable for the manuscript. CS is guarantor.

    • Funding The NEOLEV2 study was funded by the FDA 1 RO1FD004147. The REDCap database is supported by NIH Cooperative Agreement UL1TR001442. The Persyst EEG software company worked closely with the authors on the NEOLEV2 study and provided their software to the researchers free of charge but have had no input into this manuscript. The Corticare commercial EEG monitoring company worked closely with the authors on the NEOLEV2 study on a commercial basis. They have had no input into the writing of this manuscript.

    • 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.