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Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development
Burt Consultancy LLC, 2616 Erwin Rd 2405, Durham, NC 27705 USA.
Phys Comm Responsible Med, Washington, DC USA.
GSK, David Jack Ctr R&D, Translat Med, Res, Ware, Herts, England.
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2018 (English)In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 46, no 6, p. 335-346Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
FRAME , 2018. Vol. 46, no 6, p. 335-346
Keywords [en]
Accelerator Mass Spectrometry (AMS), clinical development, clinical research, clinical trials, drug development, exploratory clinical trials, exploratory investigational new drug, Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), microdosing, Phase 0, Positron Emission Tomography (PET), Three Rs, translational research
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-379246ISI: 000459832100010PubMedID: 30657329OAI: oai:DiVA.org:uu-379246DiVA, id: diva2:1296929
Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-18Bibliographically approved

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