Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans – a practical guide

ABSTRACTIntroduction: Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition.Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios.Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvemen...