Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics

Background: Accelerator mass spectrometry (AMS) is a sensitive isotope ratio technique used in drug development that allows for small levels of C-14-drug to be administered to humans, thereby removing regulatory hurdles associated with radiotracer studies. AMS uses innovative study designs to obtain pharmacokinetic and metabolism data. Objective: This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans. Methods: The review focuses on two study designs: i) administration of tracer C-14-drug intravenously with a simultaneous non-labelled extravascular therapeutic dose to obtain the pharmacokinetic parameters of clearance, volume of distribution and absolute bioavailability without extensive intravenous toxicology safety studies or formulation development; and ii) use of low levels of C-14-drug during Phase I studies to investigate the quantitative metabolism of the drug in humans early in drug development, as required by the new FDA guideline issued in February 2008. Results/conclusions: Early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.