title: Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures.
abstract: OBJECTIVE
  The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area.
  
  
  METHODS
  Children (n = 20) were given ketamine 5 or 10 mg·kg(-1) orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5-1 mg·kg(-1)) to nine children during the procedure while a further nine children were given an infusion (0.1 mg·kg(-1)·h(-1)) continued for 4-19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8-24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time-concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed-effects models.
  
  
  RESULTS
  The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 sd 2.1 years, range 1-8 years; weight 14.7 sd 4.9 kg, range 7.9-25 kg), and these children contributed 214 ketamine and norketamine observations. A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half-time was 59 (90% CI 29.4, 109.2) min and had high between-subject variability (BSV 148%). Population parameter estimates, standardized to a 70-kg person, were central volume 21.1 (BSV 47.1%) l·70 kg(-1), peripheral volume of distribution 109 (27.5%) l·70 kg(-1), clearance 81.3 (46.1%) l·h(-1)·70 kg(-1), and inter-compartment clearance 259 (50.1%) l·h(-1)·70 kg(-1). Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l·70 kg(-1) with an elimination clearance of 64.4 (BSV 63.4%) l·h(-1) ·70 kg(-1) and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h(-1)·70 kg(-1).
  
  
  CONCLUSIONS
  The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (<0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg·kg(-1) followed by intravenous ketamine 1 mg·kg(-1) i.v. with the advent of short-duration surgical dressing change at 45 min.
authors.affiliation: Department of Anaesthesia, Auckland Children's Hospital, Auckland, New Zealand.
authors.forename: Katharine E J
authors.initials: KE
authors.lastname: Brunette
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomas
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: David W
authors.initials: DW
authors.lastname: Herd
authors.forename: Simone
authors.initials: S
authors.lastname: Schulein
mesh_terms: D000284:Administration, Oral; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D001711:Biotransformation; D002056:Burns / Q000150:complications* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*
chemical_list: D000778:Anesthetics, Dissociative; D007649:Ketamine; C033419:norketamine