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Nature Reviews Drug Discovery
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Phase 0/microdosing approaches: time for mainstream application in drug development?

Nature Reviews Drug Discoveryvolume 19, pages801–818 (2020)Cite this article

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Abstract

Phase 0 approaches — which include microdosing — evaluate subtherapeutic exposures of new drugs in first-in-human studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

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Fig. 1: Phase 0/microdosing regulatory framework from ICH M3 guidelines.
Fig. 2: Phase 0 and phase I timelines.
Fig. 3: Extrapolation of subtherapeutic phase 0 data to therapeutic-level exposures.
Fig. 4: Extrapolation from microdose to therapeutic-level exposures — role of PBPK modelling.
Fig. 5: Intratarget microdosing (ITM)28,66,70.

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Acknowledgements

The authors acknowledge the members of the Phase-0/Microdosing Network, an international consortium of phase 0 stakeholders, and especially E. Baker, M. Bergström, P. Choyke, M. Croft, S. de Wildt, J. DiMasi, S. Dueker, U. Glaenzel, I. Hallett, P. T. Henderson, O. Jonas, K. Lee, M. Okour, I. Rabiner, A. Roffel, W. Vaes, E. van Duijn, B. van Groen, L. Vuong, I. Yamada and H. Yamazaki for their review and/or contribution to the formulation of the concepts in this Perspective. Some of the Phase-0/Microdosing Network’s discussions that helped refine consensus concepts included in this Perpsective were held at the First International Phase-0/Microdosing Stakeholder Meeting, 12 March 2019, Washington (DC, USA).

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Authors and Affiliations

  1. Burt Consultancy LLC. talburtmd.com, New York, NY, USA

    Tal Burt

  2. Phase-0/Microdosing Network. Phase-0Microdosing.org, New York, NY, USA

    Tal Burt

  3. GlaxoSmithKline Research and Development Ltd, Ware, UK

    Graeme Young

  4. Seoul National University, Seoul, Republic of Korea

    Wooin Lee

  5. University of Tokyo, Tokyo, Japan

    Hiroyuki Kusuhara

  6. Medical University of Vienna, Vienna, Austria

    Oliver Langer

  7. AIT Austrian Institute of Technology GmbH, Vienna, Austria

    Oliver Langer

  8. Manchester University, Manchester, UK

    Malcolm Rowland

  9. RIKEN, Yokohama, Japan

    Yuichi Sugiyama

Authors
  1. Tal Burt
  2. Graeme Young
  3. Wooin Lee
  4. Hiroyuki Kusuhara
  5. Oliver Langer
  6. Malcolm Rowland
  7. Yuichi Sugiyama

Contributions

T.B., W.L. and Y.S. contributed to researching data for this article. T.B., G.Y., W.L., O.L., H.K., M.R. and Y.S. made substantial contributions to discussion of the content, writing of the manuscript and reviewing the manuscript before submission.

Corresponding author

Correspondence toTal Burt.

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Competing interests

Y.B. is President of the Phase-0/Microdosing Network, a non-profit educational organization dedicated to phase 0 including microdosing approaches and receives fees for consultations that may be impacted by this publication. G.Y. is employed by GlaxoSmithKline Research and Development Ltd and holds shares in the company. T.B., Y.S., M.R. and O.L. are members of the Phase-0/Microdosing Network Board of Directors. All authors are members of the Phase-0/Microdosing Network.

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Phase-0/Microdosing Network:https://phase-0microdosing.org/

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Burt, T., Young, G., Lee, W.et al. Phase 0/microdosing approaches: time for mainstream application in drug development?.Nat Rev Drug Discov19, 801–818 (2020). https://doi.org/10.1038/s41573-020-0080-x

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