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 any C-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 the C-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.

An Investigation of the Metabolism and Excretion of KD101 and Its Interindividual Differences: A Microtracing Mass Balance Study in Humans

“…AMS, a highly sensitive analytical tool, has enabled for the human AME study to be performed with a trace radioactive dose 9 . As the cost of AMS‐based bioanalysis has continuously decreased, 10,11 many drug development studies have actively adopted the AMS technology 12–14 . This may facilitate faster and earlier decision making during drug development, which leads to shortened overall drug development timeline and increased efficiency 15 …”

“…9 As the cost of AMS-based bioanalysis has continuously decreased, 10,11 many drug development studies have actively adopted the AMS technology. [12][13][14] This may facilitate faster and earlier decision making during drug development, which leads to shortened overall drug development timeline and increased efficiency. 15 It is noteworthy that our results in humans were quite opposite to those reported in the mass balance study in rats with KD101.…”

Strategic, feasibility, economic, and cultural aspects of phase 0 approaches

“…With sensitivity in the attomole to zeptomole range (10 −18 to 10 −21 mole) AMS is the most sensitive analytical tool available to quantify concentrations of organic compounds in biological tissues 60 (Table 5). AMS is a tracer technology that uses radiolabeling, typically with 14 C, to discriminate between administered dose and other, non‐labeled sources of carbon, such as endogenous compounds or other administered compounds 77 . After administration of the radiolabeled compound, plasma, or other biological samples, such as biopsies, cerebrospinal fluid, bronchial lavage, and blister fluids, may be collected for AMS bioanalysis at intervals that allow the desired characterization of the compound's disposition.…”

“…Because the sample is combusted and converted to carbon dioxide in the AMS sample preparation process, AMS analysis cannot discriminate between the various molecular forms carrying the radiolabel, for example, parent compound and metabolites. However, using liquid chromatography (LC) prior to AMS sample preparation in a process called LC + AMS or high performance LC/ultraperformance LC + AMS this methodology can allow characterization of the various analytes including discrimination between the parent compound and its metabolites 17,77,78 …”

An Accelerator Mass Spectrometry‐Enabled Microtracer Study to Evaluate the First‐Pass Effect on the Absorption of YH4808

“…Additionally, when the pharmacogenomic influence of drug‐metabolizing enzymes and transporters is also investigated, a comprehensive assessment of the absorption process for a drug is possible. Therefore, the LC+AMS‐based 14 C‐labeled microtracer study, when coupled with concomitant oral administration of a nonradiolabeled drug at a therapeutic dose, enables information‐rich studies about the definitive pharmacokinetic readouts of a drug at an early development stage …”