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The determination and interpretation of the therapeutic index in drug development

Nature Reviews Drug Discovery volume 11, pages 751–761 (2012)Cite this article

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Abstract

A key part of drug discovery and development is the characterization and optimization of the safety and efficacy of drug candidates to identify those that have an appropriately balanced safety–efficacy profile for a given indication. The therapeutic index (TI) — which is typically considered as the ratio of the highest exposure to the drug that results in no toxicity to the exposure that produces the desired efficacy — is an important parameter in efforts to achieve this balance. Various types of safety and efficacy data are generated in vitro and in vivo (in animals and in humans), and these data can be used to predict the clinical TI of a drug candidate at an early stage. However, approaches to systematically and quantitatively compare these types of data and to apply this knowledge more effectively are needed. This article critically discusses the various aspects of TI determination and interpretation in drug development for both small molecule drugs and biotherapeutics.

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Figure 1: An exposure-centric approach to therapeutic index determination.
Figure 2: The therapeutic index in relation to the pharmacodynamic end point.

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Acknowledgements

The authors would like to thank B. Schmouder, L. Urban, P. Bouchard, P. Hoffmann, P. Heining and V. Jarugula for their valuable input and in-depth interdisciplinary discussions on this topic.

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  1. Patrick Y. Muller and Mark N. Milton are at the Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.,

    Patrick Y. Muller & Mark N. Milton

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Correspondence to Patrick Y. Muller.

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Supplementary information S1 (table)

To convert umol/L to ng/mL: multiply umol/L value by MW of compound. (XLSX 50 kb)

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Muller, P., Milton, M. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 11, 751–761 (2012). https://doi.org/10.1038/nrd3801

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