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

作者：Mooij Miriam G; van Duijn Esther; Knibbe Catherijne A J; Windhorst Albert D; Hendrikse N Harry; Vaes Wouter H J; Spaans Edwin; Fabriek Babs O; Sandman Hugo; Grossouw Dimitri; Hanff Lidwien M; Janssen Paul J J M; Koch Birgit C P; Tibboel Dick; de Wildt Saskia N^*

来源：Clinical Pharmacokinetics, 2014, 53(11): 1045-1051.

DOI：10.1007/s40262-014-0176-8

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. %26lt;br%26gt;Objective The objective of this study was to present pilot data of an oral [C-14] paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children. %26lt;br%26gt;Methods In an open-label microdose pharmacokinetic pilot study, infants (0-6 years of age) received a single oral [C-14] 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 [C-14] AAP and metabolites ([C-14] AAP-Glu and [C-14] AAP-4Sul) were measured by accelerator mass spectrometry. %26lt;br%26gt;Results Ten infants (aged 0.1-83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [C-14] AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (C-max) [C-14] AAP 1.68 (0.75-4.76) ng/L, [C-14] AAP-Glu 0.88 (0.34-1.55) ng/L, and [C-14] AAP-4Sul 0.81 (0.29-2.10) ng/L. Dose-normalized oral [C-14] 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. %26lt;br%26gt;Conclusions We demonstrate the feasibility of using a [C-14] labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.

• 出版日期2014-11