title: The pharmacokinetics of intravenous paracetamol in neonates: size matters most.
abstract: BACKGROUND
  The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates.
  
  
  METHODS
  A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27-45 weeks' postmenstrual age (PMA)) was undertaken using non-linear mixed effects models. Data from three published studies were pooled with newly collected time-concentration points during repeated intravenous paracetamol administration.
  
  
  RESULTS
  A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%.
  
  
  CONCLUSIONS
  Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32-44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential.
authors.affiliation: Neonatal Intensive Care Unit, University Hospital, Herestraat 49, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Greta M
authors.initials: GM
authors.lastname: Palmer
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood*; D001835:Body Weight; D004334:Drug Administration Schedule; D005865:Gestational Age; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000097:blood / Q000188:drug therapy; D007275:Injections, Intravenous; D008954:Models, Biological; D010146:Pain / Q000097:blood* / Q000188:drug therapy
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen