title: Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age.
abstract: BACKGROUND
  There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration.
  
  
  METHODS
  An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml(-1), 2 mg kg(-1) in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time-concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6-2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time-concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models.
  
  
  RESULTS
  Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h(-1) 70 kg(-1), volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg(-1), absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg(-1). Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h(-1) 70 kg(-1), volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg(-1), absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg(-1). There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) microg ml(-1) for total levobupivacaine and 0.09 (CV 37%) microg ml(-1) for unbound levobupivacaine.
  
  
  CONCLUSIONS
  Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.
authors.affiliation: Department of Anaesthesia and Pain Management, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Chalkiadis
authors.forename: B J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: M
authors.initials: M
authors.lastname: Tay
authors.forename: A
authors.initials: A
authors.lastname: Bjorksten
authors.forename: J J
authors.initials: JJ
authors.lastname: Kelly
mesh_terms: D000375:Aging / Q000097:blood; D000763:Anesthesia, Caudal; D000779:Anesthetics, Local / Q000097:blood*; D001835:Body Weight / Q000502:physiology; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000077554:Levobupivacaine; D008297:Male
chemical_list: D000779:Anesthetics, Local; D000077554:Levobupivacaine; D002045:Bupivacaine