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

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

Correlation of NICU anthropometry in extremely preterm infants with brain development and language scores at early school age

Abstract Growth in preterm infants in the neonatal intensive care unit (NICU) is associated with increased global and regional brain volumes at term, and increased postnatal linear growth is associated with higher language scores at age 2. It is unknown whether these relationships persist to school age or if an association between growth and cortical metrics exists. Using regression analyses, we investigated relationships between the growth of 42 children born extremely preterm (< 28 weeks gestation) from their NICU hospitalization, standardized neurodevelopmental/language assessments at 2 and 4–6 years, and multiple neuroimaging biomarkers obtained from T1-weighted images at 4–6 years. We found length at birth and 36 weeks post-menstrual age had positive associations with language scores at 2 years in multivariable linear regression. No growth metric correlated with 4–6 year assessments. Weight and head circumference at 36 weeks post-menstrual age positively correlated with total brain volume and negatively with global cortical thickness at 4–6 years of age. Head circumference relationships remained significant after adjusting for age, sex, and socioeconomic status. Right temporal cortical thickness was related to receptive language at 4–6 years in the multivariable model. Results suggest growth in the NICU may have lasting effects on brain development in extremely preterm children

Motivations for and Against Participation in Neonatal Research: Insights from Interviews of Diverse Parents Approached for Neonatal Research in the US.

Objective To describe parents’ motivations for and against participation in neonatal research, including the views of those who declined participation. Study design We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation. Results Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a “guinea pig” were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations. Conclusions Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes

Pharmacokinetics of Levetiracetam in Neonates with Seizures

The pharmacokinetics of levetiracetam were determined prospectively in 18 neonates with seizures. Neonates were found to have lower clearance, higher volume of distribution, and a longer half-life as compared with older children and adults. Mild somnolence was the only adverse effect

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)