Adding value through accelerator mass spectrometry-enabled first in human studies.

Accelerator mass spectrometry (AMS) is an ultra-sensitive technique for the analysis of radiocarbon. It is applicable to bioanalysis of any 14 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 14 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.

Accelerator MS: its role as a frontline bioanalytical technique.

Accelerator MS (AMS) is an ultrasensitive technique that can be used to quantify (14)C in biological samples. Prior to analysis, the carbon in samples is selectively isolated, with the result that the technique is independent of compound structure and nonsusceptible to matrix effects. AMS is a tracer technique and therefore can be used to quantify all compound-related material without the need to develop extraction or chromatographic separation methods. Thus AMS has some distinct advantages over conventional assay techniques, such as LC-MS/MS. AMS also complements conventional techniques, facilitating innovative, cost-effective clinical study designs. Thus, metabolism data can be obtained from early clinical trials, identifying any human metabolites that may raise safety concerns. By administration of an intravenous (14)C microtracer dose concomitantly with an extravascular dose of nonradiolabeled compound, AMS can also be used to determine absolute bioavailability and intravenous pharmacokinetic parameters without the need for intravenous toxicology or formulation development.