title: 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.
abstract: 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 improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.
authors: a Burt Consultancy , LLC , Durham , NC , USA.
authors: Tal
authors: T
authors: Burt
authors: b Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD , USA.
authors: Christy S
authors: CS
authors: John
authors: c Pacific Pharma Group, LLC , 1402 S. Brookside Terrace, Tacoma , WA , USA.
authors: Jon L
authors: JL
authors: Ruckle
authors: d LTV Consulting , Davis , CA , USA.|e BioCore Co, Ltd. , Seoul , Korea.
authors: Le T
authors: LT
authors: Vuong
mesh_terms: D004347:Drug Interactions; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods*; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
keywords: Accelerator mass spectrometer (AMS); Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS); Microdosing; Phase-0; Positron Emission Tomography (PET); clinical development; clinical research; clinical trials; drug development; exploratory Investigational New Drug (eIND); exploratory clinical trials; translational research