Opportunities in Low-Level Radiocarbon Microtracing: Applications and New Technology

Abstract

14C-radiolabeled (radiocarbon) drug studies are central to defining the disposition of therapeutics in clinical development. Concerns over radiation, however, have dissuaded investigators from conducting these studies as often as their utility may merit. Accelerator mass spectrometry (AMS), originally designed for carbon dating and geochronology, has changed the outlook for in-human radiolabeled testing. The high sensitivity of AMS affords human clinical testing with vastly reduced radiative (microtracing) and chemical exposures (microdosing). Early iterations of AMS were unsuitable for routine biomedical use due to the instruments’ large size and associated per sample costs. The situation is changing with advances in the core and peripheral instrumentation. We review the important milestones in applied AMS research and recent advances in the core technology platform. We also look ahead to an entirely new class of 14C detection systems that use lasers to measure carbon dioxide in small gas cells.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance

“…Currently, AMS analysis is carried out in facilities generally separated from the laboratories that are dedicated to metabolite structure elucidation. Smaller benchtop AMS instruments with more facile sample preparation are being developed (Synal et al, 2007;Vuong et al, 2016), with this, microtracer studies could become more regularly used in drug development. It could also enable ADME studies to be done earlier in the clinical program which would yield earlier quantitative metabolite profiles useful for MIST decision-making.…”

Metabolism and Excretion of GCC-4401C, a Factor Xa Inhibitor, in Humans

“…Clinical testing was conducted at PRA Health Sciences (at that time located in Zuidlaren, The Netherlands; currently in Groningen, The Netherlands). The use of a microtracer dose expedited timelines by reducing the human radiation burden to exempted levels that did not require human dosimetry estimates based upon animal tissue distribution data [10,11].…”

Evaluation of cAMS for 14 C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

“…This approach would also potentially allow the conduct of ADME type investigations in special populations like children, infants, pregnant women or elderly, where the administering of higher amounts of radioactivity is prohibited [9]. Also, the technology could be applied to study the ADME fate of entities with a very long half-life, like for example biologics [38] or modified biologics like antibody-drug conjugates.…”

“…AMS is a highly sensitive method for the detection of radioactive 14 C, and this technology allows human clinical studies to be performed at radiochemical exposures that do not differ substantially from the natural background of radioactivity [8,9]. In general, AMS using graphitization of sample carbon (gAMS) has been accepted by health authorities as a method to provide data for human ADME studies [10,11].…”