Structural identifiability and indistinguishability analysis as tools for quantitative and systems pharmacology to support the 3Rs

This proposal aims to overcome recognised limitations in the modelling of toxicological processes by introducing and applying established and novel systems modelling tools and techniques to exemplar problems in toxicology. The project will provide a more robust generic analytical framework to improve parameter estimation, sensitivity, robustness, reliability and validity of models in toxicology. In turn this step change in modelling will enhance experiment design, improve risk and safety assessment and thus help support the 3Rs of animal use. This research will be supported by industry (AstraZeneca) and will be applied to models for the improvement of both human and animal safety. This work will provide new tools and seed the emergence of a new field, namely quantitative and systems toxicology.

Bergenholm L et al. (2016). PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data. Journal of Pharmacological and Toxicological Methods 79:34-44. doi: 10.1016/j.vascn.2016.01.002

Janzén DL et al. (2016). Parameter Identifiability of Fundamental Pharmacodynamic Models. Frontiers in Physiology 7:590. doi: 10.3389/fphys.2016.00590

Janzén DL et al. (2016). Three novel approaches to structural identifiability analysis in mixed-effects models. Computer Methods and Programs in Biomedicine 171:141-152. doi: 10.1016/j.cmpb.2016.04.024

Collins TA et al. (2015). Modeling and simulation approaches for cardiovascular function and their role in safety assessment. CPT Pharmacometrics Syst Pharmacol. 4(3):e00018. doi: 10.1002/psp4.18

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Strategic grant

Status:

Closed

Principal investigator

Dr Michael Chappell

Institution

University of Warwick

Co-Investigator

Dr Neil Evans

Grant reference number

NC/K001205/1

Award date:

Apr 2013 - Apr 2016

Grant amount

£245,378 (Co-funded by EPSRC)