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

Introduction: 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.

KEYWORDS:

• Accelerator mass spectrometer (AMS)
• clinical development
• clinical research
• clinical trials
• drug development
• exploratory clinical trials
• exploratory Investigational New Drug (eIND)
• Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS)
• Microdosing
• Phase-0
• Positron Emission Tomography (PET)
• translational research

Article highlights

• Phase-0/Microdosing trials are a regulatory pathway that allows First-in-Human (FIH) testing of new drugs using exposures in the sub-therapeutic range. This allows for safer, quicker, and cheaper development solutions.

• The past decade has witnessed increasing number of validation studies and applications of these approaches in drug development of new and old pharmaceuticals.

• Sensitive analytic tools, such as Accelerator Mass Spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) are required to determine drug disposition of the low systemic exposures.

• A wide range of study methodologies and design options is used to accommodate the advantages and disadvantages of PET, AMS, and LC-MS/MS and their combination to optimize execution of study objectives.

• Applications include study of pharmacokinetic (PK) and pharmacodynamic (PD) properties, target localization, drug-drug interactions (DDIs), effects in vulnerable populations (e.g. pediatric), and Intra-Target Microdosing (ITM).

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Declaration of interest

T Burt holds the patent for Intra-Target Microdosing (ITM). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.