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

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.

• Authors: Lawrence C Ku, Christoph P Hornik, Ryan J Beechinor, James M Chamberlain, Jeffrey T Guptill, Barrie Harper, Edmund V Capparelli, Karen Martz, Ravinder Anand, Michael Cohen-Wolkowiez, Daniel Gonzalez, Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee
• Journal: CPT: pharmacometrics & systems pharmacology (CPT Pharmacometrics Syst Pharmacol) Vol. 7 Issue 11 Pg. 718-727 (11 2018) ISSN: 2163-8306 [Electronic] United States
• PMID: 30267478 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Anticonvulsants
• Lorazepam
• Diazepam

Topics

• Administration, Intravenous
• Adolescent
• Anticonvulsants (pharmacokinetics, therapeutic use)
• Child
• Child, Preschool
• Diazepam (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Infant
• Lorazepam (pharmacokinetics, therapeutic use)
• Male
• Prospective Studies
• Status Epilepticus (drug therapy)