Pediatric Microdose Study of [(14)C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-014-0176-8) contains supplementary material, which is available to authorized users.