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Developing drug prototypes: pharmacology replaces safety and tolerability?

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From Nature Reviews Drug Discovery

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Abstract

New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I– Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management.

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Figure 1: The account of the foxglove and its medical uses.
Figure 2: Determining the prototypical nature of a project.
Figure 3: Linear non-translational development.
Figure 4: Representation of ascending dose study design.
Figure 5: Translational drug development.
Figure 6: A first-in-human pharmacology experiment.
Figure 7: A schematic to determine the objectives using the question-based approach.

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Acknowledgements

I am indebted to my close colleagues at the Centre for Human Drug Research, Leiden, The Netherlands, particularly J. van Gerven and K. Burggraaf, for their input in the ideas that form the basis for this article. M. Kenter, D. Breimer and P. van Brummelen provided constructive criticism and suggestions.

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  1. Adam F. Cohen is at the Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands, and at the Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands. ac@chdr.nl,

    Adam F. Cohen

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FURTHER INFORMATION

AstraZeneca's Annual Report 2006

Central Committee on Research Involving Human Subjects

Note for Guidance on Repeated Toxicity (CPMP/SWP/1042/99)

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Cohen, A. Developing drug prototypes: pharmacology replaces safety and tolerability?. Nat Rev Drug Discov 9, 856–865 (2010). https://doi.org/10.1038/nrd3227

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