Nature Reviews Drug Discovery
September 8, 2020
Tal Burt, Graeme Young, Wooin Lee et al.
101 citations
Phase 0 approaches, including microdosing, are early-stage clinical trials that test very low, subtherapeutic doses of new drugs in humans to gather safety and pharmacological data before larger studies. Traditionally used to assess pharmacokinetics, these methods now also help understand a drug's mechanism of action and pharmacodynamics. Phase 0 trials can improve the selection of drug candidates for further development, making the process safer, cheaper, quicker, and more informed. While challenges like extrapolating results to therapeutic doses and managing development timelines remain, the authors suggest that phase 0 approaches should be considered for most drug development scenarios.
Expert Opinion on Drug Metabolism & Toxicology
April 4, 2013
Graham Lappin, Robert J. Noveck, Tal Burt
97 citations
Microdosing uses inherently safe, sub-pharmacologic doses of drug to acquire exploratory pharmacokinetic data in humans early in drug development. A decade after the first microdose data publication, evidence suggests microdosing may predict human pharmacokinetics better than alternative methods. Combining microdosing with physiologically based modeling could yield more reliable future predictions. The concept has been applied to drug-drug interactions, polymorphism, and assessing drug concentrations over time at the site of action. Microdosing may offer additional unanticipated benefits not yet fully realized.
BMC Pulmonary Medicine
September 1, 2024
Tom M. Quinn, Annya M. Bruce, Tal Burt et al.
Phase 0 trials, positioned between preclinical research and phase I, test sub-clinical microdoses in humans to gather early pharmacokinetic, pharmacodynamic, and mechanistic data, improving drug development efficiency and reducing animal testing. Traditional phase 0 trials use sub-therapeutic microdoses administered intravenously, with readouts from accelerator mass spectrometry, liquid chromatography tandem mass spectrometry, and whole-body positron emission tomography. Mathematical models extrapolate pharmacokinetic data for larger doses but are limited for pharmacodynamic and target engagement data. An Intra-Target Microdosing approach exposes a small body compartment to potentially clinically active local concentrations, enabling pharmacodynamic data collection and target engagement evidence, with potential for rapid, cost-effective development of new and repurposed drugs in the pulmonary system.