Abstract
There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison (“read-across”), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX (“electronic toxicity”) consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables.
Highlights
Shortcomings of Toxicology in Current Drug DevelopmentThe main barrier for a new drug to enter into clinical development is the preclinical evaluation of toxicity, where the systemic rodent and non-rodent toxicity studies are the pivotal investigation paradigms (as described in various guidelines e.g. International Conference of Harmonisation Topic M3 (R2)) [1]
35% of all drug development projects fail as a result of toxicity detected during preclinical safety studies [2], animal studies are an important safeguard for the safety of patients
In order to front-load identification of toxic effects into earlier phases of development, where several candidates are under investigation and lead compounds can still be modified, in vitro screening assays have been developed for a variety of toxicological endpoints
Summary
Shortcomings of Toxicology in Current Drug DevelopmentThe main barrier for a new drug to enter into clinical development is the preclinical evaluation of toxicity, where the systemic rodent and non-rodent toxicity studies are the pivotal investigation paradigms (as described in various guidelines e.g. International Conference of Harmonisation Topic M3 (R2)) [1]. In order to front-load identification of toxic effects into earlier phases of development, where several candidates are under investigation and lead compounds can still be modified, in vitro screening assays have been developed for a variety of toxicological endpoints (for an overview see [3]). While predictive screening assays are useful for endpoints such as genotoxicity and hERG inhibition, the complex interplay of factors that lead to systemic or organ toxicity in vivo is not effectively represented in vitro. Assays for phospholipidosis [4], off-target pharmacology profiling and inhibition of the hERG channel [5] in vitro are useful to identify hazards and contribute to the design of more hypothesis-driven in vivo studies. While in vitro approaches can offer a certain mechanistic insight, they are rarely able to provide risk assessment information for the in vivo situation, i.e., a decision to terminate a compound or a chemical series is rarely based on the outcome of such assays
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