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Updated: Apr 18, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with
Colin R Garner1,2, Kevin B Park3, Neil S French3
1Hull York Medical School, University of York, Heslington York, YO1 5DD, United Kingdom.
Insights
Pediatric pharmacokinetic studies compared [14C]-paracetamol (14C-PARA) administration via therapeutic dose versus microdose in infants. Results showed pharmacokinetic parameters were within a two-fold range, suggesting microdosing advantages.
Area of Science:
- Pharmacology
- Paediatric Medicine
- Analytical Chemistry
Background:
- Paediatric drug development requires accurate pharmacokinetic data.
- Microdosing offers potential ethical and safety benefits for paediatric studies.
- Accelerator Mass Spectrometry (AMS) is a sensitive bioanalytical technique.
Purpose of the Study:
- To compare paediatric pharmacokinetics (PK) of [14C]-paracetamol (14C-PARA) when administered as a therapeutic dose versus a microdose.
- To further develop and validate AMS bioanalysis for the 0-2 year old age group.
- To assess the feasibility of microdosing in paediatric pharmacokinetic studies.
Main Methods:
- Administered [14C]-PARA via enteral or i.v. routes in microdoses or mixed with therapeutic doses to infants.
- Measured [14C]-PARA concentrations in small plasma samples (10-15 µl) using AMS.
- Included 34 infants across oral microdose, i.v. microdose, oral therapeutic, and i.v. therapeutic groups.
Main Results:
- Mean clearance (CL) values ranged from 1.46 to 2.93 L/h.
- Half-life (t1/2) values varied between 2.55 h and 8.36 h.
- Dose-normalized AUC(0-t) values were between 0.54 and 0.90 (mg L-1 h).
Conclusions:
- Paediatric pharmacokinetic parameters for [14C]-PARA were within a two-fold range for both therapeutic and microdoses.
- Microdosing in paediatric pharmacokinetic studies may offer ethical and safety advantages.
- AMS bioanalysis is validated for use in infants aged 0-2 years.
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.
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