Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development
Tal Burt, Le Thuy Vuong, Elizabeth Baker, Graeme C. Young, A. Daniel McCartt, Mats Bergström, Yuichi Sugiyama, Robert Combes
Alternatives to Laboratory Animals December 1, 2018 DOI: 10.1177/026119291804600603 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Microdosing |
| Key findings | The authors argue that Phase 0 approaches, including microdosing, have advanced in applications, methodology, operations, and drug development culture. They contend these approaches enable safer, quicker, cheaper first-in-human testing, improve extrapolation from microdose to therapeutic exposures, and can reduce animal testing through early termination of development. |
Abstract
Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development. In the operational area, the increased sensitivity of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), expansion of the utility of Positron Emission Tomography (PET) imaging, and the introduction of Cavity Ring-Down Spectroscopy (CRDS), have led to the increased accessibility and utility of Phase 0 approaches, while reducing costs and exposure to radioactivity. PET has extended the application of microdosing, from its use as a predominant tool to record pharmacokinetics, to a method for recording target expression and target engagement, as well as cellular and tissue responses. Advances in methodology include adaptive Phase 0/Phase 1 designs, cassette and cocktail microdosing, and Intra-Target Microdosing (ITM), as well as novel modelling opportunities and simulations. Importantly, these methodologies increase the predictive power of extrapolation from microdose to therapeutic level exposures. However, possibly the most challenging domain in which progress has been made, is the culture of drug development. One of the main potential values of Phase 0 approaches is the opportunity to terminate development early, thus not only applying the principle of ‘kill-early-kill-cheap’ to enhance the efficiency of drug development, but also obviating the need for the full package of animal testing required for therapeutic level Phase 1 studies. Finally, we list developmental scenarios that utilised Phase 0 approaches in novel drug development.
Comparable studies
Other narrative reviews on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Big physics, small doses: the use of AMS and PET in human microdosing of development drugs | 2003 | Review | |
| Phase 0/microdosing approaches: time for mainstream application in drug development? | 2020 | Review | |
| Microdosing and drug development: past, present and future | 2013 | Review | |
| Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development | 2016 | Review | |
| Expectancy Effects in Psychedelic Trials. | 2024 | Review |
Citations in the library
Cites 15
- Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development European Journal of Clinical Pharmacology September 1, 2003
- Big physics, small doses: the use of AMS and PET in human microdosing of development drugs Nature Reviews Drug Discovery February 28, 2003
- Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs Clinical Pharmacology & Therapeutics September 1, 2006
- Identification of the Rate-Determining Process in the Hepatic Clearance of Atorvastatin in a Clinical Cassette Microdosing Study Clinical Pharmacology & Therapeutics August 10, 2011
- Microdosing and drug development: past, present and future Expert Opinion on Drug Metabolism & Toxicology April 4, 2013
and 10 more in the library