Modeling approaches for reducing safety-related attrition in drug discovery and development: a review on myelotoxicity, immunotoxicity, cardiovascular toxicity, and liver toxicity.

:Safety and tolerability is a critical area where improvements are needed to decrease the attrition rates during development of new drug candidates. Modeling approaches, when smartly implemented, can contribute to this aim.:The focus of this review was on modeling approaches applied to four kinds of drug-induced toxicities: hematological, immunological, cardiovascular (CV) and liver toxicity. Papers, mainly published in the last 10 years, reporting models in three main methodological categories - computational models (e.g., quantitative structure-property relationships, machine learning approaches, neural networks, etc.), pharmacokinetic-pharmacodynamic (PK-PD) models, and quantitative system pharmacology (QSP) models - have been considered.:The picture observed in the four examined toxicity areas appears heterogeneous. Computational models are typically used in all areas as screening tools in the early stages of development for hematological, cardiovascular and liver toxicity, with accuracies in the range of 70-90%. A limited number of computational models, based on the analysis of drug protein sequence, was instead proposed for immunotoxicity. In the later stages of development, toxicities are quantitatively predicted with reasonably good accuracy using either semi-mechanistic PK-PD models (hematological and cardiovascular toxicity), or fully exploited QSP models (immuno-toxicity and liver toxicity).