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Chemical Structure-Based and Toxicogenomic Models

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Genotoxicity and Carcinogenicity Testing of Pharmaceuticals

Abstract

All pharmaceuticals undergo a comprehensive panel of non-clinical tests to ensure their safety before being approved for use in humans. Genetic toxicity and carcinogenicity testing in whole animal and cell-based assays are a significant component of this testing and the outcome of these studies can significantly impact the marketability of a drug product. Consequently, there is a strong desire for pharmaceutical developers to assess the potential of new drug candidates to cause these effects prior to investing significant resources and in advance of regulatory submission. Early screening of pharmaceutical candidates can be performed through the application of computational methods that evaluate the relationship between chemical structural descriptors and genotoxic and/or carcinogenic outcomes. (Quantitative) structure-activity relationship [(Q)SAR] models represent an entirely virtual assessment that relies only on knowledge of chemical structure to provide a prediction, making them inexpensive and rapid to apply without the need for synthesis of the potential drug candidate. Toxicogenomic-based approaches aim to assess biological functions based on interactions among various parts of biological systems with emphasis on molecular pathways. Toxicogenomics consists of interrogating pathways via studying the genome-wide gene expression changes, and is the most widely explored systems biology methodology in carcinogenicity and genotoxicity risk assessment. It is typically performed at later stages of the drug development process to interpret chemical exposure-induced perturbations of biological pathways by identifying molecular initiating events that can predict downstream genotoxic and carcinogenic consequences, as well as address the question of human relevance of non-clinical safety findings. Although the qualification of toxicogenomic-based approaches for regulatory use is being pursued by industry and regulatory agencies, the application of these methodologies is currently limited to exploratory analyses by pharmaceutical developers. In contrast, in addition to their application to early drug discovery, (Q)SAR models are now being routinely utilized under harmonized regulatory guidance for the late-stage safety assessment of drug substance impurities.

This chapter provides an overview of the use of chemical structure-based and toxicogenomic-based methods in pharmaceutical development, with a focus on the endpoints of genetic toxicity and carcinogenicity.

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Authors and Affiliations

  1. US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, 20993, USA

    Lidiya Stavitskaya & Naomi L. Kruhlak

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, 06355, USA

    Jiri Aubrecht

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  1. Lidiya Stavitskaya
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Correspondence to Naomi L. Kruhlak .

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Editors and Affiliations

  1. Vice- President of Drug Safety Evaluation, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Michael J. Graziano

  2. ToxRox Consulting, McLean VA 22101, Virginia, USA

    David Jacobson-Kram

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Stavitskaya, L., Aubrecht, J., Kruhlak, N.L. (2015). Chemical Structure-Based and Toxicogenomic Models. In: Graziano, M., Jacobson-Kram, D. (eds) Genotoxicity and Carcinogenicity Testing of Pharmaceuticals. Springer, Cham. https://doi.org/10.1007/978-3-319-22084-0_2

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