M. G. Mooij,1 E. Van Duijn,2 C. A. Knibbe,3 A. D. Windhorst,4 N. H. Hendrikse,4 W. H. Vaes,2 E. Spaans,1 B. O. Fabriek,2 H. Sandman,2 D. Grossouw,2 L. M. Hanff,5 P. J. Janssen,5 B. C. Koch,6 D. Tibboel,1 S. N. De Wildt1; 1Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands, 2TNO, Zeist, Netherlands, 3Leiden University, Leiden, Netherlands, 4VU University Medical Center, Amsterdam, Netherlands, 5Erasmus MC - Hospital Pharmacy, Rotterdam, Netherlands, 6Erasmus MC - hospital pharmacy, Rotterdam, Netherlands

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. We aimed to present pilot data of an oral [14C]paracetamol (AAP) microdosing study as proof of concept to study developmental pharmacokinetics in children.
METHODS: In an open microdose pharmacokinetic pilot study, infants (0-6 yrs of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg IV q6h). Blood samples were taken from an indwelling catheter. AAP blood levels were measured by LC-MS/MS and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.
RESULTS: Ten infants (age 0.1 to 83.1 months) were included, one was excluded as he vomited shortly after administration. In 9 patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) Cmax [14C]AAP 1.68 ng/L (0.75-4.76), [14C]AAP-Glu 0.88 ng/L (0.34-1.55), and [14C]AAP-4Sul 0.81 ng/L (0.29-2.10). Dose normalized [14C]AAP Cmax approached median Cav intravenous concentrations: 8.41 mg/L (3.75-23.78 mg/L) and 8.87 mg/L (3.45-12.9 mg/L), respectively.
CONCLUSION: We demonstrate the practical and ethical feasibility to use a [14C]labeled microdose to study paracetamol pharmacokinetics, including metabolite disposition, in young children.