Computational chemistry approach for the early detection of drug‐induced idiosyncratic liver toxicity

Abstract

Idiosyncratic drug toxicity (IDT), considered as a toxic host‐dependent event, with an apparent lack of dose response relationship, is usually not predictable from early phases of clinical trials, representing a particularly confounding complication in drug development. Albeit a rare event (usually ca. 78 to 86% of correctly classified drugs. An LDA‐based desirability analysis was carried out in order to select the levels of the predictor variables needed to trigger the more desirable drug, i.e. the drug with lower potential for idiosyncratic hepatotoxicity. Finally, two external test sets were used to evaluate the ability of the models in discriminating toxic from nontoxic structurally and pharmacologically related drugs and the ability of the best model (LDA) in detecting potential idiosyncratic hepatotoxic drugs, respectively. The computational approach proposed here can be considered as a useful tool in early IDT prognosis. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008