Exploratory toxicology as an integrated part of drug discovery. Part I: Why and how.

Toxicity and clinical safety have major impact on drug development success. Moving toxicological studies into earlier phases of the R&D chain prevents drug candidates with a safety risk from entering clinical development. However, to identify candidates without such risk, safety has to be designed actively. Therefore, we argue that toxicology should be fully integrated into the discovery process. We describe our strategy, including safety assessment of novel targets, selection of chemical series without inherent liabilities, designing out risk factors and profiling of candidates, and we discuss considerations regarding what to screen for. We aim to provide timely go/no-go decisions (fail early) and direction to the discovery teams, by steering away from safety risk (showing what will not fail).

Exploratory toxicology as an integrated part of drug discovery. Part II: Screening strategies.

In an effort to reduce toxicity-related attrition, different strategies have been implemented throughout the pharmaceutical industry. Previously (in Part I), we have outlined our 'integrated toxicology' strategy, which aims to provide timely go/no-go decisions (fail early) but also to show a direction to the drug discovery teams (showing what will not fail). In this review (Part II of the series) we describe our compound testing strategies with respect to cardiovascular safety, hepatotoxicity, genotoxicity, immunotoxicity and exploratory in vivo toxicity. We discuss the in vitro, ex vivo and in vivo assays and models we employ to assess safety risks and optimize compound series during the drug discovery process, including their predictivity and the decisions they generate.