Pediatric microdose and microtracer studies using ¹⁴C in Europe

Abstract

Important information gaps remain on the efficacy and safety of drugs in children. Pediatric drug development encounters several ethical, practical, and scientific challenges. One barrier to the evaluation of medicines for children is a lack of innovative methodologies that have been adapted to the needs of children. This article presents our successful experience of pediatric microdose and microtracer studies using (14) C-labeled probes in Europe to illustrate the strengths and limitations of these approaches.

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

“…Potential limitations, however, include difficulty correlating PK between microdoses and therapeutic doses because of saturable drug transporters and drug‐metabolizing enzymes, and (if radiolabeled drugs are chosen) limited pediatric safety data . Despite concerns with radiation, however, the estimated radioactive exposure from a theoretical microdose of a 14 C drug with a half‐life of 40 days is 0.33‐0.8 μSV, which is significantly less than a chest x‐ray (12 μSV) . Two European initiatives studied the use of 14 C‐paracetamol (acetaminophen) and 14 C‐midazolam microdose probes in neonates/children, and the preliminary data show good study feasibility and acceptable PK linearity between microdoses and therapeutic doses .…”

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

“…The much higher sensitivity of AMS further reduces sampling requirements (as little as 2 μl per sample, depending on drug concentration). Radiation exposure is low with PET and extremely low with AMS, consistent with normal background exposure . Finally, the ethics argument needs to be strengthened by scientific necessity and exposure to no more than minimal risk over that expected in usual daily activities.…”

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

“…Recent efforts have focused on determining the dose linearity of several drugs to evaluate the feasibility of using AMS microdosing for drug development. 61, 62, 66 …”

“…The potential for microdosing using AMS in children was first reported in a review by Vuong et al in which a 14 C-labeled ursodiol microdosing study was conducted in infants. 69 Recent efforts to demonstrate microdosing feasibility in children have included PAMPERS (Paediatric Accelerator Mass Spectrometry Evaluation Research Study) and PEDMIC (Pediatric Microdosing: elucidating age-related changes in oral absorption to guide dosing of new formulations) 66 . The PAMPERS project is evaluating the feasibility of both microdosing and microtracer studies in children using 14 C-paracetamol and 14 C-midazolam, two drugs that are well characterized and commonly prescribed to children.…”