17 Microdosing/microtracer based pediatric drug development

Introduction: An overview is given on the use of microdosing/microtracing studies for the safer and faster development of drugs in children. In a microdosing study a very small amount of radiolabelled (often 14C) drug is administered to a human volunteer. Using accelerator mass spectrometry extremely low amounts of the drug and metabolites can be traced and quantified.

Methods: Several publications show the feasibility of microdose/microtrace studies in the pediatric population, providing insight into the ontogenic differences between all age groups. So far well-known drugs have been used for these studies in children, such as midazolam and paracetamol. Information was generated on the absolute bioavailability, mass balance and metabolite profiles.

Results: In pediatric drug development especially metabolic pathways raise a challenge, as between age groups the expression levels and activity of metabolizing enzymes can differ significantly. In 2019 the FDA released a draft of the “General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products Guidance for Industry”. This document includes the recommendation to perform microdosing studies in neonates to assess ontogenic differences in the metabolic pathways compared to older populations.

Conclusions: The classic approach of developing a drug for the pediatric population is time consuming, as each age class, starting from human adults down to neonates is investigated consecutively. Using a microdosing approach information in all age groups could be generated in parallel without increasing safety risks, when dose linearity for the drug of interest is shown adults. Thereby providing the most accurate “prediction model” for drug behavior at therapeutic levels.