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

on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

Research output: Contribution to journalArticle

Abstract

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. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200–600 ng/mL.

Original languageEnglish (US)
Pages (from-to)718-727
Number of pages10
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume7
Issue number11
DOIs
StatePublished - Nov 1 2018

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Pharmacokinetics
Pediatrics
Status Epilepticus
Diazepam
Efficacy
Safety
Compartment Model
Labels
Clinical Trials
Population
Dose
Target
Model
Range of data
Lorazepam
Simulation
Body Size
Relationships
Children
Therapeutics

All Science Journal Classification (ASJC) codes

  • Modeling and Simulation
  • Pharmacology (medical)

Cite this

on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. / Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus. In: CPT: Pharmacometrics and Systems Pharmacology. 2018 ; Vol. 7, No. 11. pp. 718-727.
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abstract = "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. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200–600 ng/mL.",
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on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee 2018, 'Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus', CPT: Pharmacometrics and Systems Pharmacology, vol. 7, no. 11, pp. 718-727. https://doi.org/10.1002/psp4.12349

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus. / on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 7, No. 11, 01.11.2018, p. 718-727.

Research output: Contribution to journalArticle

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T1 - Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

AU - on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

AU - Ku, Lawrence C.

AU - Hornik, Christoph P.

AU - Beechinor, Ryan J.

AU - Chamberlain, James M.

AU - Guptill, Jeffrey T.

AU - Harper, Barrie

AU - Capparelli, Edmund V.

AU - Martz, Karen

AU - Anand, Ravinder

AU - Cohen-Wolkowiez, Michael

AU - Gonzalez, Daniel

AU - Furda, Gary

AU - Benjamin, Danny

AU - Kearns, Gregory L.

AU - Paul, Ian M.

AU - Sullivan, Jan

AU - Hornik, Christoph P.

AU - Paul, Ian

AU - Siegel, David

AU - Taylor-Zapata, Perdita

AU - Zajicek, Anne

AU - Ren, Zhaoxia

AU - Tsilou, Ekaterini

AU - Pagan, Alice

AU - Simone, Gina

AU - Ku, Lawrence

AU - Mills, Mary

AU - Watt, Kevin

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N2 - 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. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200–600 ng/mL.

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