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Clin Transl Sci. 2016 Apr;9(2):74-88. doi: 10.1111/cts.12390. Epub 2016 Mar 30.

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development.

Author information

Principal, Burt Consultancy, Durham, NC, 27705, USA.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Oak Ridge Institution for Science and Education (ORISE) Fellow.
Visiting Professor of Pharmacology School of Pharmacy University of Lincoln, Joseph Banks Laboratories, Lincoln, LN6 7DL, UK.
Principal, LTV Consulting, Davis, CA, USA.
Clinical Advisor at BioCore, Seoul, South Korea.
Intensive Care and Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, M13 9PT, UK.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, USA.


A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.

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