Abstract
In drug development, it is important to mitigate toxicity risks detected in nonclinical studies or estimate human risk. In vitro evaluation is widely used for toxicity risk assessment because it has some advantages including required less amount of drug substance, high throughput, and the ability to use human cell/tissue. However, they also have several challenges such as reproducing the toxic phenotypes observed in vivo studies. In recent years, various complex in vitro models (CIVM), including organ-on-chip and organoid systems have been developed. These models are utilized for evaluating toxic responses which used to be difficult to assess using simple in vitro systems alone. In addition, need for animal alternative methods is expected under the FDA Modernization Act 2.0. Whereas, we have observed several issues in their application during the early stage of drug discovery. Additionally, since CIVM is based on a "phenotype" approach like in vivo toxicity studies, it is difficult to elucidate the mechanisms underlying toxic responses in some cases. To solve this problem, one possible approach would be to understand molecular initiating events (MIE), which can be applied to relatively simple in vitro evaluation systems. In this presentation, we would like to discuss the strategic use and future prospects of complex/simple in vitro models to efficiently understand and mitigate toxicity risks.
