title: Adding value through accelerator mass spectrometry-enabled first in human studies.
abstract: Accelerator mass spectrometry (AMS) is an ultra-sensitive technique for the analysis of radiocarbon. It is applicable to bioanalysis of any14C-labelled analyte and any sample type. The increasing body of data generated using LC+AMS indicates that the methodology is robust and reliable, and capable of meeting the same validation criteria as conventional bioanalytical techniques. Because it is a tracer technique, AMS is capable of discriminating between an administered radiolabelled dose and endogenous compound or non-radiolabelled compound administered separately. This paper discusses how it can be used to enhance the design of first in human (FIH) clinical studies and generate significant additional data, including: fundamental pharmacokinetics (CL and V), absolute bioavailability, mass balance, routes and rates of excretion, metabolic fate (including first-pass metabolism, identification of biliary metabolites and quantitative data to address metabolite safety testing issues), and tissue disposition of parent compound and metabolites. Because the14C-labelled microtracer dose is administered at the same time as a pharmacologically relevant non-radiolabelled dose, there is no concern about dose-linearity. However the mass of the microtracer dose itself is negligible and therefore does not affect the outcome of the FIH study. The addition of microtracer doses to a FIH study typically requires little additional expense, apart from the AMS analytics, making the approach cost-effective. It can also save significant time, compared to conventional approaches, and, by providing reliable human in vivo data as early as possible, prevent unnecessary expenditure later in drug development.
authors.affiliation: PharMAS Consulting, Harrogate, UK.
authors.forename: Mark A
authors.identifier: 0000-0003-3545-7070
authors.initials: MA
authors.lastname: Seymour
mesh_terms: D000054:Acceleration; D001682:Biological Availability; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D019275:Radiopharmaceuticals
keywords: AMS; absolute bioavailability; accelerator mass spectrometry; human in vivo disposition; intravenous pharmacokinetics; microtracer