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

Journal Article · · Clinical and Translational Science
DOI:https://doi.org/10.1111/cts.12390· OSTI ID:1376052
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8]
  1. Burt Consultancy, Durham, NC (United States)
  2. US Food and Drug Administration, Silver Spring MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology (OCP), Office of Translational Sciences; Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
  3. Univ. of Lincoln (United Kingdom). School of Pharmacy, Joseph Banks Lab.
  4. LTV Consulting, Davis CA (United States); BioCore, Seoul (South Korea)
  5. US Food and Drug Administration, Silver Spring MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology (OCP), Office of Translational Sciences
  6. Erasmus MC Sophia Children's Hospital, Rotterdam (The Netherlands)
  7. RIKEN Innovation Center, Yokohama, Kanagawa (Japan). Sugiyama Lab.
  8. Univ. of Manchester (United Kingdom). Centre for Applied Pharmacokinetic Research; Univ. of California, San Francisco, CA (United States). Dept. of Bioengineering and Therapeutic Sciences
+ Show Author Affiliations

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. Lastly, 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.

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC); Netherlands Organisation for Health Research (ZonMw)
OSTI ID:
1376052
Journal Information:
Clinical and Translational Science, Vol. 9, Issue 2; ISSN 1752-8054
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 54 works
Citation information provided by
Web of Science

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Cited By (8)

A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach journal July 2019
Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans – a practical guide journal September 2016
Multimodal nanoparticle imaging agents: design and applications
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Better science for safer medicines: the human imperative journal October 2018
Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail journal November 2018
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Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies journal October 2018

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