title: Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model.
abstract: OBJECTIVE
  Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range.
  
  
  METHODS
  Morphine and morphine-3-glucuronide (M3G) concentration data from 358 (pre)term neonates, infants, children and adults, and morphine concentration data from 117 adolescents were analysed using NONMEM 7.2. Based on available data, two models were developed: I. using morphine data; II. using morphine and M3G data.
  
  
  RESULTS
  In model I, morphine clearance across the paediatric age range was very well described by a BDE function in which the allometric exponent decreased in a sigmoidal manner with bodyweight (BDE model) from 1.47 to 0.88, with half the decrease in exponent reached at 4.01 kg. In model II, the exponent for the formation and elimination clearance of M3G was found to decrease from 1.56 to 0.89 and from 1.06 to 0.61, with half the decrease reached at 3.89 and 4.87 kg, respectively. Using the BDE model, there was no need to use additional measures for size or age.
  
  
  CONCLUSIONS
  The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age ranges between (pre)term neonates and adults by allowing the allometric exponent to decrease across the paediatric age range from values higher than 1 for neonates to values lower than 1 for infants and children.
authors.affiliation: LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sadhavisvam
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D001835:Body Weight; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D009020:Morphine / Q000493:pharmacokinetics*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine