New models and applications in predictive toxicology

抄録

Hazard identification for pharmaceutical agents has moved earlier into the pipeline, as more predictive toxicology tools are developed and implemented. Attrition analysis indicates that the cardiovascular system, liver, CNS, GI and kidney are among the most common adverse effects observed.    The increased pressure to de-risk the portfolio has presented an opportunity for newly developed human-focused in vitro tools that permit a greater functional perspective than cell lines and even conventional primary cell cultures.  Specifically, human derived iPSC cells have been developed to examine the potential of compounds to impact pro-arrhythmia, as well as contractility.  Similarly, individual and population-based effects, such as disease can be incorporated into risk assessment.  In vitro derived biomarkers can be used to anchor observed adverse effects across in vitro observations, in vivo nonclinical species and patient responses.  The prediction of liver toxicity in human both in clinical trials and post-marketing has proven difficult in part due to the contribution of multiple cell and individual characteristics.  The switch from 2D to 3D culture of liver cells has improved the predictivity of this de-risking activity.  For the GI system, organoids have proven useful in assessing human and nonclinical species GI toxicity potential.  The judicious application of new in silico and in vitro tools, such as iPSC cells and organoids within the drug discovery process will enable a greater likelihood of success across the drug development continuum.