title: Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis.
abstract: OBJECTIVE
  The aims of the study were to compare [(14)C]-paracetamol ([(14)C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0-2 year old age group.
  
  
  METHODS
  [(14)C]-PARA concentrations in 10-15 µl plasma samples were measured after enteral or i.v. administration of a single [(14)C]-PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen.
  
  
  RESULTS
  Thirty-four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h(-1), 1.76 (1.07) l h(-1), 2.93 (2.08) l h(-1) and 2.72 (3.10) l h(-1), t(1/2) values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0-t) (mg l(-1) h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26).
  
  
  CONCLUSIONS
  All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg(-1)) and a microdose (ng kg(-1)) in babies between 35 to 127 weeks post-menstrual age. [(14)C]-PARA pharmacokinetic parameters were within a two-fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies.
authors.affiliation: Hull York Medical School, University of York, Heslington York, YO1 5DD, United Kingdom.|United Kingdom and Garner Consulting, 5 Hall Drive, Sand Hutton, York, YO41 1LA, United Kingdom.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Garner
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Park
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom.
authors.forename: Neil S
authors.initials: NS
authors.lastname: French
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Earnshaw
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool, L12 2AP, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Selby
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool, L12 2AP, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Byrne
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool, L12 2AP, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Siner
authors.affiliation: Good Clinical Practice Alliance - Europe, Schoolbergenstraat 47, BE-3010, Kessel-Lo, Belgium.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Crawley
authors.affiliation: TNO Zeist, Utrechtseweg 48, PO Box 360, 3700, AJ Zeist, The Netherlands.
authors.forename: Wouter H J
authors.initials: WH
authors.lastname: Vaes
authors.affiliation: TNO Zeist, Utrechtseweg 48, PO Box 360, 3700, AJ Zeist, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van Duijn
authors.affiliation: TNO Zeist, Utrechtseweg 48, PO Box 360, 3700, AJ Zeist, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: deLigt
authors.affiliation: Department of Paediatrics, Tartu University Hospital, University of Tartu, 51014, Tartu, Estonia.
authors.forename: Heili
authors.initials: H
authors.lastname: Varendi
authors.affiliation: Department of Paediatrics, Tartu University Hospital, University of Tartu, 51014, Tartu, Estonia.
authors.forename: Jane
authors.initials: J
authors.lastname: Lass
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793, Warsaw, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grynkiewicz
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793, Warsaw, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Maruszak
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, University of Liverpool, Liverpool, L69 3BX, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Turner
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D061605:Administration, Intravenous; D000284:Administration, Oral; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D013058:Mass Spectrometry
chemical_list: D002250:Carbon Radioisotopes; D000082:Acetaminophen
keywords: accelerator mass spectrometry; exploratory clinical study; microdosing; paediatric pharmacokinetics; paracetamol