Pharmacokinetics of Levetiracetam in Neonates with Seizures

Neonatal seizures are a common problem in the first month of life. Phenobarbital is still the most frequently used medication to treat neonatal seizures,1 despite evidence that it causes neuronal apoptosis in animal models2 and may have long-term adverse effects on neurodevelopment.3 Levetiracetam (Keppra; UCB Pharma Inc, Smyrna, Georgia) is an anticonvulsant medication with a good safety and efficacy profile in adults and older children.4, 5, 6 Levetiracetam has linear pharmacokinetics, is mainly excreted unchanged by the kidneys, and is metabolized via enzymatic hydrolysis by a plasma esterase. Case series suggest that levetiracetam may be safe in the treatment of neonatal seizures,7, 8, 9, 10, 11 but no pharmacokinetic studies have been performed in this population. The purpose of this study was to determine the pharmacokinetics of levetiracetam and to gather preliminary safety data in neonates with seizures. Methods The institutional review boards at Cincinnati Children\u27s Hospital Medical Center and Good Samaritan Hospital approved the protocol and written informed consent was obtained from the legal guardian of all subjects. We prospectively enrolled infants ≤30 days of age and ≥32 weeks gestational age with seizures treated with levetiracetam who were admitted to the neonatal intensive care unit. Exclusion criteria included birth weight \u3c2000 g and known creatinine level ≥2.0 mg/dL. Consent was obtained for the blood draws before the levetiracetam dose was given. All subjects received at least 20 mg/kg of phenobarbital before receiving levetiracetam. The levetiracetam dose was determined by the clinician prescribing the drug. Blood sampling was conducted with a D-optimal sparse sampling design with 3 samples collected in each patient. Patients were divided in 3 groups to obtain informative time points in the entire dosing interval. Levetiracetam concentrations were determined by using a validated liquid chromatography-electrospray tandem mass spectrometry assay.12 Non-linear mixed effects modeling (NONMEM, version 7.1, ICON Dev Soln, Ellicott City, Maryland) was used to perform the pharmacokinetic analyses. Individual Bayesian pharmacokinetic parameter estimates were calculated with MW/Pharm software (version 3.60, MediWare, Gronigen, The Netherlands). SAS software (version 9.2, SAS Institute, Cary, North Carolina) was used to analyze associations between demographic and pharmacokinetic parameters (Appendix; available at www.jpeds.com). Safety assessments included physical examination before and 24 hours after the loading dose of levetiracetam and closely monitoring vital signs after the loading dose for 24 hours. Adverse events were identified by means of bedside nurse reports and medical record review. Results A total of 21 infants who received levetiracetam for clinical seizure control, electrographic seizure control, or both were screened for the study from October 2008 to May 2010, and 19 of these infants were enrolled. The two patients who were not enrolled received levetiracetam before consent could be obtained. One subject was excluded because of a laboratory error. Pharmacokinetic data included 54 levetiracetam measurements from 18 subjects. Patient characteristics are summarized in Table I. The initial loading doses ranged from 14.4 to 39.9 mg/kg