Format

Send to

Choose Destination
Br J Clin Pharmacol. 2015 Jul;80(1):157-67. doi: 10.1111/bcp.12597. Epub 2015 Jun 1.

Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis.

Author information

1
Hull York Medical School, University of York, Heslington York, YO1 5DD, United Kingdom.
2
United Kingdom and Garner Consulting, 5 Hall Drive, Sand Hutton, York, YO41 1LA, United Kingdom.
3
Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom.
4
Alder Hey Children's NHS Foundation Trust, Eaton Road, West Derby, Liverpool, L12 2AP, United Kingdom.
5
Good Clinical Practice Alliance - Europe, Schoolbergenstraat 47, BE-3010, Kessel-Lo, Belgium.
6
TNO Zeist, Utrechtseweg 48, PO Box 360, 3700, AJ Zeist, The Netherlands.
7
Department of Paediatrics, Tartu University Hospital, University of Tartu, 51014, Tartu, Estonia.
8
Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793, Warsaw, Poland.
9
Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, University of Liverpool, Liverpool, L69 3BX, United Kingdom.

Abstract

AIMS:

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.

KEYWORDS:

accelerator mass spectrometry; exploratory clinical study; microdosing; paediatric pharmacokinetics; paracetamol

PMID:
25619398
PMCID:
PMC4500335
DOI:
10.1111/bcp.12597
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center