Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

Published

Journal Article

BACKGROUND: 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. METHODS: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. RESULTS: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. CONCLUSIONS: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

Full Text

Duke Authors

Cited Authors

  • 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,

Published Date

  • August 2017

Published In

Volume / Issue

  • 56 / 8

Start / End Page

  • 941 - 951

PubMed ID

  • 27943220

Pubmed Central ID

  • 27943220

Electronic International Standard Serial Number (EISSN)

  • 1179-1926

Digital Object Identifier (DOI)

  • 10.1007/s40262-016-0486-0

Language

  • eng

Conference Location

  • Switzerland