title: Pediatric microdose study of [(14)C]paracetamol to study drug metabolism using accelerated mass spectrometry: proof of concept.
abstract: BACKGROUND
  Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.
  
  
  OBJECTIVE
  The objective of this study was to present pilot data of an oral [(14)C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children.
  
  
  METHODS
  In an open-label microdose pharmacokinetic pilot study, infants (0-6 years of age) received a single oral [(14)C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and [(14)C]AAP and metabolites ([(14)C]AAP-Glu and [(14)C]AAP-4Sul) were measured by accelerator mass spectrometry.
  
  
  RESULTS
  Ten infants (aged 0.1-83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [(14)C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (C max) [(14)C]AAP 1.68 (0.75-4.76) ng/L, [(14)C]AAP-Glu 0.88 (0.34-1.55) ng/L, and [(14)C]AAP-4Sul 0.81 (0.29-2.10) ng/L. Dose-normalized oral [(14)C]AAP C max approached median intravenous average concentrations (C av): 8.41 mg/L (3.75-23.78 mg/L) and 8.87 mg/L (3.45-12.9 mg/L), respectively.
  
  
  CONCLUSIONS
  We demonstrate the feasibility of using a [(14)C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Room Sp-3458, Wytemaweg 80, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Mooij
authors.forename: Esther
authors.initials: E
authors.lastname: van Duijn
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: Wouter H J
authors.initials: WH
authors.lastname: Vaes
authors.forename: Edwin
authors.initials: E
authors.lastname: Spaans
authors.forename: Babs O
authors.initials: BO
authors.lastname: Fabriek
authors.forename: Hugo
authors.initials: H
authors.lastname: Sandman
authors.forename: Dimitri
authors.initials: D
authors.lastname: Grossouw
authors.forename: Lidwien M
authors.initials: LM
authors.lastname: Hanff
authors.forename: Paul J J M
authors.initials: PJ
authors.lastname: Janssen
authors.forename: Birgit C P
authors.initials: BC
authors.lastname: Koch
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D061605:Administration, Intravenous; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid / Q000379:methods; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009426:Netherlands; D010865:Pilot Projects; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D018712:Analgesics, Non-Narcotic; D002250:Carbon Radioisotopes; D000082:Acetaminophen