Title
Observational infant exploratory [14C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis
Author
Garner, C.R.
Park, K.B.
French, N.S.
Earnshaw, C.
Schipani, A.
Selby, A.M.
Byrne, L.
Siner, S.
Crawley, F.P.
Vaes, W.H.J.
van Duijn, E.
de ligt, R.
Varendi, H.
Lass, J.
Grynkiewicz, G.
Maruszak, W.
Turner, M.A.
Publication year
2015
Abstract
Aims The aims of the study were to compare [14C]-paracetamol ([14C]-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 [14C]-PARA concentrations in 10-15 μl plasma samples were measured after enteral or i.v. administration of a single [14C]-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, t1/2 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. [14C]-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. © 2015 The British Pharmacological Society.
Subject
Life
MSB - Microbiology and Systems Biology
ELSS - Earth, Life and Social Sciences
Healthy for Life
Biology
Healthy Living
Exploratory clinical study
Microdosing
Paediatric pharmacokinetics
Paracetamol
Unclassified drug
Accelerator mass spectrometry
Area under the curve
Child
Drug blood level
Drug clearance
Drug half life
Female
Human
Infant
Major clinical study
Male
Mass spectrometry
Maximum plasma concentration
Pharmacokinetics
Plasma concentration-time curve
Time to maximum plasma concentration
Ultra performance liquid chromatography
Volume of distribution
To reference this document use:
http://resolver.tudelft.nl/uuid:64a7e42f-b2ad-489b-93c1-c3a60ea7b1ea
DOI
https://doi.org/10.1111/bcp.12597
TNO identifier
527065
ISSN
0306-5251
Source
British Journal of Clinical Pharmacology, 80 (1), 157-167
Document type
article