The Use of Microdosing in the Development of Small Organic and Protein Therapeutics

Microdosing uses very low, radionuclide-labeled drug doses for early human imaging or pharmacokinetic studies, requiring only a reduced preclinical toxicology package to lower cost and speed development. The approach limits exposure and risk by testing small populations for short periods. However, extrapolating results to therapeutic doses demands special attention to low-dose behavior, especially for small organic molecules versus protein therapeutics. The article reviews these aspects and discusses microdosing's role in drug development according to three pillars: tissue distribution and target access, target engagement, and induction of relevant tissue responses.

Study at a glance

Abstract

Microdosing as a regulatory concept was introduced to facilitate exploratory studies in humans. The concept involves the use of very low doses of a radionuclide-labeled compound for imaging studies or for assessing plasma pharmacokinetics using equipment that has a highly sensitive readout. The supporting principle is that use of these low doses for a limited time in well-controlled, small populations will limit exposure and have a low risk of adverse effects. Microdosing regulations specify a reduced preclinical toxicology-assessment package in order to shorten the route to human studies and reduce its cost. However, for extrapolation to therapeutically relevant doses and plasma concentrations, there are specific aspects of the use of these low doses and low plasma concentrations that require special attention. These specific aspects are reviewed in this article, with separate attention being paid to small organic molecules and protein therapeutics. The indications for microdosing in drug development are discussed in terms of the 3 pillars of survival in drug development, the first of which is characterization of tissue distribution and access to the site of action; the second, engagement of the target; and the third, induction of tissue responses relevant to a therapeutic response.