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

Publication Type
Journal Article
Year of Publication
2018
Authors
Ku, Lawrence C; Hornik, Christoph P; Beechinor, Ryan J; Chamberlain, James M; Guptill, Jeffrey T; Harper, Barrie; Capparelli, Edmund V; Martz, Karen; Anand, Ravinder; Cohen-Wolkowiez, Michael; Gonzalez, Daniel; The Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee
Secondary
CPT Pharmacometrics Syst Pharmacol
Volume
7
Start Page
718
Pagination
718-727
Date Published
11/2018
Keywords
children; diazepam; status epilepticus (SE)
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.