Microdosing: a valuable tool for accelerating drug development and the role of bioanalytical methods in meeting the challenge.

The concept of specifically determining the clinical pharmacokinetics of a compound using a very low nonpharmacologically active dose (microdose) with an abridged safety and chemistry, manufacturing and control package is relatively new. It is not without its controversy and it is still a subject of discussion. Here, the rationale and application of this approach are examined, together with the regulatory and bioanalytical framework. There are two bioanalytical methods commonly used for human microdosing studies: LC-MS/MS and accelerator MS (AMS). Each method has advantages and disadvantages with the choice of instrumentation being closely tied to the primary objective(s) of the study. If a rapid decision is required on the appropriateness of a pharmacokinetic profile or if a choice is needed from a series of compounds, especially before radiolabeled material is available, LC-MS/MS may be preferable. However, if extreme sensitivity is required, data are required on all drug-related material and metabolites, or a simultaneous intravenous microdose is used to determine absolute bioavailability (sometimes referred to as microtracing), AMS becomes the analytical method of choice. Examples are provided of microdosing studies utilizing both of these bioanalytical techniques. It is emphasized that microdosing is only one tool in the drug developer's tool box and it should be used in the context of all available data. However, when used appropriately, microdosing is a valuable tool, bridging between lead optimization and early clinical development.