In Vitro Toxicology: Next Generation Models and Methods to Improve Safety Evaluation

With the advent of molecular and cellular toxicology, the field of drug safety evaluation has been undergoing an important paradigm shift, which has recently been further incentivized through legislation. In vitro approaches are regularly used for internal decision making and as a means to de-risk, or at least better understand, the safety profile of compounds via investigative toxicology studies. These approaches now have the potential to mitigate some of the blind spots of traditional in vivo approaches and bolster preclinical safety evaluation. For each major physiological system or function, namely, the heart, central nervous system, endocrine system, gastrointestinal system, hematopoietic system and immune function, kidney, liver, male and female reproductive systems and teratogenicity, in vitro approaches using cell lines, human induced pluripotent stem cell (hiPSC)-derived cells, and tissue preparations or organoids, and microphysiological systems (MPS) are discussed in order of increasing complexity to provide a comprehensive overview of the tools currently available. Because this is an emerging field, it is not possible to provide standard protocols and endpoints as these must be tailored to the specific in vitro model and target organ system, and therefore, potential uses, technical considerations, and possible drawbacks of recent models are discussed instead. When possible, assays that have been more broadly established and become part of standard practices are also presented. As in vitro toxicology approaches continue to be improved and refined, safety evaluation will become more robust and both companies and patients will benefit.