title: Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Division of Emergency Medicine, Children's National Medical Center, Washington, DC, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Chamberlain
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.|Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Guptill
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.|Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Barrie
authors.initials: B
authors.lastname: Harper
authors.affiliation: Emmes Corporation, Rockville, MD, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0831, USA. ecapparelli@ucsd.edu.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008140:Lorazepam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D011446:Prospective Studies; D012984:Software / Q000706:statistics & numerical data; D013226:Status Epilepticus / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D008140:Lorazepam