Non-clinical animal toxicity studies continue to be used routinely to evaluate the safety of pharmaceuticals, and are mandated by regulatory guidelines, but they have important limitations. Their use in early drug discovery, when there is abundant chemical choice, is not practical, and they are unable to detect many clinically significant human toxicities (most notably, idiosyncratic human adverse drug reactions). In vitro methods that use human cells, and assess mechanistically relevant endpoints, have the potential to address these limitations. Useful in vitro assays for genotoxicity, skin sensitisation and eye irritancy have already been developed, and have been incorporated into regulatory guidelines. Exciting progress has also been made in the development of useful in vitro human cardiotoxicity and drug-induced liver injury (DILI) assays. It will now be important to ensure that the utility of these assays, for the prediction of human cardiotoxicity and DILI, is accepted by the scientific community and that they gain regulatory acceptance.

Safety Assessment of Pharmaceuticals

Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness. Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted. Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.

Human biology-based drug safety evaluation: scientific rationale, current status and future challenges

/pdf/reducing-attrition-through-early-assessment-of-drug-safety-5drjme4yen.pdf

Reducing attrition through early assessment of drug safety

Reducing attrition through early assessment of drug safety: Highlights from the Society of Medicines Research Symposium, held on March 13th, 2014 - National Heart & Lung Institute, Kensington, London, U.K.

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Reducing attrition through early assessment of drug safety

Reducing attrition through early assessment of drug safety: Highlights from the Society of Medicines Research Symposium, held on March 13th, 2014 - National Heart & Lung Institute, Kensington, London, U.K.