What is AZ’s main focus?
The academia-industry hybrid environment in TransQST enabled AZ, together with other consortium members, to develop novel mathematical and biological modelling solutions that maximize study subject’s safety during drug development. In particular, we were interested in optimizing the use of preclinical information by developing mathematical models to facilitate the transition from preclinical to clinical phase and support trial design decisions such as doses and dosing regimens.
What has participated in TransQST meant for your company?
TransQST consortium has offered a multidisciplinary working space where advanced modelling techniques have been developed, with multidisciplinary input from the consortium members, and put to the test in realistic toxicology scenarios. In AZ, this project has provided the opportunity to develop multiscale models able to integrate data of different sources obtained in a variety of in-vitro and in-vivo preclinical settings.
What challenges has AZ faced across the project?
The pandemic interrupted our vibrant general in-person meetings which were fantastic opportunities to discuss scientific emergent ideas. Predicting and mitigating GI toxicity is usually very challenging in preclinical stages and requires expensive clinical assessment in many cases.
What are your main achievements in TransQST?
One of our main achievements was to innovate in the field of modelling gastrointestinal toxicity by developing a suite of multiscale models with capacity to predict clinical toxicity at early stages of development.
In addition, in close collaboration with other consortium members we contributed to test and refine novel modelling approaches of drug induced toxicity for kidney, liver and heart within a realistic drug development context.
Which TransQST outcome/s would you highlight? Why?
We would highlight the development of an agent-based model, which is a relatively novel modeling technology in the field of pharmacology. The model describes single cell dynamics and integrates various molecular processes within each cell to enable the simulation of molecular perturbations induced by cytotoxic drugs, resulting in a cascade of disruptive events spanning from the cell cycle to single cell arrest and/or apoptosis, perturbation of cell migration, altered cell turnover and ultimately loss of epithelial integrity and clinical diarrhea.
What do you believe is the main contribution of TransQST in the field?
The project has enhanced the application of Quantitative Systems Toxicology (QST) model within an industrial context to improve mechanistic understanding and prediction of safety liabilities of new drug candidates at early stages of the drug development pipeline.