title: Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants.
abstract: OBJECTIVE
  The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation.
  
  
  METHODS
  Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites.
  
  
  RESULTS
  A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h.
  
  
  CONCLUSIONS
  Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Máxima Medical Centre, Veldhoven, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: van Ganzewinkel
authors.forename: L
authors.initials: L
authors.lastname: Derijks
authors.forename: K J S
authors.initials: KJ
authors.lastname: Anand
authors.forename: R A
authors.initials: RA
authors.lastname: van Lingen
authors.forename: C
authors.initials: C
authors.lastname: Neef
authors.forename: B W
authors.initials: BW
authors.lastname: Kramer
authors.forename: P
authors.initials: P
authors.lastname: Andriessen
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D061605:Administration, Intravenous; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D005978:Glutathione / Q000097:blood / Q000652:urine; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008111:Liver Function Tests; D009426:Netherlands; D059408:Pain Management / Q000379:methods*
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D005978:Glutathione
keywords: Acetaminophen; Newborn; Pain; Paracetamol; Preterm