Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds.

Use of human tissue in ADME and safety profiling of development candidates.

The clinical success of a compound is often curtailed because of inadequate safety, pharmacokinetics or efficacy. Human tissue can be used to identify the potential shortcomings of new drugs before they undergo testing in man. This review highlights the consent and ethical approval required for the use of human tissues and discusses their use for predicting human ADME and safety profiles of drugs in preclinical development.