Seizures

Population Pharmacokinetic Modeling of Oxcarbazepine and Its Active Metabolite 10-Monohydroxy Derivative to Inform Dosing in Children with Obesity

Posted on by Jeannine Sato

Clinical Pharmacokinetics, November 2025

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Sinha J, Zimmerman K, Balevic SJ, Hornik C, Muller WJ, Rathore M, Meyer M, Finkelstein Y, Al-Uzri A, Lakhotia A, Goldstein S, Chen JY, Anand R, Gonzalez D; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.

Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking. This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension.

Physiologically Based Pharmacokinetic Modeling of Oxcarbazepine to Characterize Its Disposition in Children with Obesity

Posted on by Jeannine Sato

Journal of Clinical Pharmacology, September 2025

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Maglalang PD, Sinha J, Helfer VE, Edginton A, Zimmerman K, Hornik CD, Muller WJ, Rathore M, Benjamin DK Jr, Chen JY, Anand R, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. 

Oxcarbazepine (OXC) is a second-generation antiseizure medication, effective through its active metabolite, 10-mono-hydroxy derivative (MHD). OXC is used as adjunctive therapy for focal-onset and primary generalized tonic-clonic seizures, with recommended dosing based on age and body weight. This study uses physiologically based pharmacokinetic (PBPK) modeling and leverages pharmacokinetic (PK) data acquired from children enrolled in pragmatic trials to understand dosing and subsequent exposure requirements in children with obesity. 

Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity

Posted on by Jeannine Sato

Journal of Clinical Pharmacology, April 2025

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McCann SM, Wen J, Balevic SJ, Muller WJ, Al-Uzri A, Hornik CD, Meyer ML, Anderson SG, Payne EH, Turdalieva S, Chamberlain JM, Gonzalez D; Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee.

Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing.

Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • June 2024

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Maglalang PD, Sinha J, Zimmerman K, McCann S, Edginton A, Hornik CP, Hornik CD, Muller WJ, Al-Uzri A, Meyer M, Chen L, Anand R, Perrin E, Gonzalez D., Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee

Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity

Posted on by Kayla Korzekwinski

The Journal of Pediatric Pharmacology and Therapeutics • December 2023

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Zimmerman KO, Wu H, Maharaj A, Turner A, Chen L, Hornik CD, Arnold S, Muller W, Al-Uzri A, Meyer M, Shiloh-Malawsky Y, Taravath S, Lakhotia A, Joshi C, Jackman J, Hornik CP; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network

This study sought to characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

Posted on by Kayla Korzekwinski

CPT Pharmacometrics & Systems Pharmacology • November 2018

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Ku LC, Hornik CP, Beechinor RJ, Chamberlain JM, Guptill JT, Harper B, Capparelli EV, Martz K, Anand R, Cohen-Wolkowiez M, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice.

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • August 2017

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Gonzalez D, Chamberlain JM, Guptill JT, Cohen-Wolkowiez M, Harper B, Zhao J, Capparelli EV; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE.

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

Posted on by Kayla Korzekwinski

Journal of Pediatrics • August 2016

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Hornik CP, Benjamin DK Jr, Smith PB, Pencina MJ, Tremoulet AH, Capparelli EV, Ericson JE, Clark RH, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act—Pediatric Trials Network.

This was a retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

Adverse Events After Routine Immunization of Extremely Low Birth Weight Infants

Posted on by Kayla Korzekwinski

JAMA Pediatrics • August 2016

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DeMeo SD, Raman SR, Hornik CP, Wilson CC, Clark R, Smith PB
Immunization of extremely low birth weight (ELBW) infants in the neonatal intensive care unit (NICU) is associated with adverse events including fever and apnea/bradycardia in the immediate post-immunization period. This presents a diagnostic dilemma for clinicians, leading to the potential for immunization delay and sepsis evaluations. The goal of this study is to compare the incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death among immunized ELBW infants in the 3 days pre- and post-immunization.

Cefepime and Ceftazidime Safety in Hospitalized Infants

Posted on by Kayla Korzekwinski

The Pediatric Infectious Disease Journal • August 2015

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Arnold CJ, Ericson J, Cho N, Tian J, Wilson S, Chu VH, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee.

Cefepime and ceftazidime are cephalosporins used for the treatment of serious Gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants. We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups.