Structural Identifiability and Indistinguishability Analysis as Tools for Quantitative and Systems Pharmacology to Support the 3Rs
Lead Research Organisation:
University of Warwick
Department Name: Sch of Engineering
Abstract
Animals are extensively used in toxicology testing to assess safety and risk of the process examined on humans and the environment. It is estimated that over 1 million animals are used across Europe each year in toxicology tests with around one fifth of all animals used in the UK involved in such tests. The mainstream use of valid, robust mathematical models that can be used with greater fidelity and confidence than those currently used in practice to accurately simulate the outcomes of such tests would therefore clearly have huge impacts on the number of animals required in the future, supporting the replacement and reduction of the use of animals in toxicology testing experiments and providing step changes in animal welfare.
This proposal aims to overcome certain shortcomings that exist in the modelling of toxicological processes by introducing and applying established and novel systems modelling tools and techniques namely structural identifiability and indistinguishability analyses. These tools have proven ability to improve the fidelity of models in terms of confidence in parameter estimation and optimising experiment design. These techniques will be applied to exemplar problems in toxicology that will provide a more robust generic analytical framework to improve parameter estimation, sensitivity, robustness, reliability and validity of these models. In turn this step change in modelling will enhance experiment design, improve risk and safety assessment and thus help support the replacement, reduction and refinement 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.
This proposal aims to overcome certain shortcomings that exist in the modelling of toxicological processes by introducing and applying established and novel systems modelling tools and techniques namely structural identifiability and indistinguishability analyses. These tools have proven ability to improve the fidelity of models in terms of confidence in parameter estimation and optimising experiment design. These techniques will be applied to exemplar problems in toxicology that will provide a more robust generic analytical framework to improve parameter estimation, sensitivity, robustness, reliability and validity of these models. In turn this step change in modelling will enhance experiment design, improve risk and safety assessment and thus help support the replacement, reduction and refinement 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.
Technical Summary
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 replacement, reduction and refinement (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.
Planned Impact
This research programme will apply new and established systems modelling tools to enhance the validity and credibility of mathematical models developed for analysing toxicological processes. This will provide new and comprehensive insights into the application and development and fidelity of models that can faithfully reproduce the kinetics and dynamics present in processes used to support toxicological testing. Consequentially this should substantially enhance the knowledge base in this important field, providing improved in-silico methods for assessing safety factors and associated risks of toxins in humans, animals and the environment. The application of innovative tools in this field will yield new knowledge that will be disseminated through international journal and conference publications, a website devoted to the project, seminars at the host and collaborative industrial organisations, collaborative contacts with other researchers and participation in professional body events The work also provides fundamental ideas and tools to seed a new research field in Quantitative and Systems Toxicology.
The research will have significant impact on the health of humans, in terms of improved knowledge of drug safety, and supporting the 3Rs by replacing, reducing and refining the number of animals used in risk assessment and safety factor experiments. In turn this will, through the use of more safe, effective and efficacious drugs, improve quality of life. The research outcomes have the potential to support changes in policy in terms of safety and risk assessment techniques applied in toxicology and in the use of animals in experimentation. Ultimately this research has the potential to guide worldwide changes in the analysis of the effects of toxins, helping to place the UK at the forefront in this field internationally.
This research will support the enhanced development of mathematical models in toxicology that can be used with greater confidence and credibility both practically and in a predictive capability to support experimental research in the risk of the use and presence of toxins across a variety of societal fields. Most notably this will help to ensure the safer use of pharmaceuticals for humans and animals and the effects of toxins on ecology and the environment in terms of the risks on flora and fauna, with wider impacts on plant and food security. In particular the research will help to generate more valid models of toxicological processes that should permit confident, robust prediction of the effects of different dose levels which will in turn has the potential to offer enormous impact on the replacement, reduction and refinement of the use of animals in experiments, currently the main means of ascertaining such effects.
This research will improve methodologies applied within toxicology testing to improve the skills of those employed to perform analysis of safety and risk assessments associated with toxins. This will also promote the wider use of mathematical modelling within industries and groups associated with toxicology, offering the potential for wider employment and training opportunities in the relevant sectors for those with skills in the use and application of systems modelling.
This research has the potential to improve wealth creation in terms of the development of safer, more effective and efficacious drugs. It also has the potential to dramatically reduce the current costs required to support animal experimentation in safety testing through the mainstream application of more robust and valid modelling tools and techniques, replacing highly expensive experimentation. This has the potential for the creation of new companies to support modelling in toxicology and, through current relevant industrial sectors, enhance wealth creation within industries and agencies such as the pharmaceutical industry, the agricultural industry, water companies and providers and environment agencies.
The research will have significant impact on the health of humans, in terms of improved knowledge of drug safety, and supporting the 3Rs by replacing, reducing and refining the number of animals used in risk assessment and safety factor experiments. In turn this will, through the use of more safe, effective and efficacious drugs, improve quality of life. The research outcomes have the potential to support changes in policy in terms of safety and risk assessment techniques applied in toxicology and in the use of animals in experimentation. Ultimately this research has the potential to guide worldwide changes in the analysis of the effects of toxins, helping to place the UK at the forefront in this field internationally.
This research will support the enhanced development of mathematical models in toxicology that can be used with greater confidence and credibility both practically and in a predictive capability to support experimental research in the risk of the use and presence of toxins across a variety of societal fields. Most notably this will help to ensure the safer use of pharmaceuticals for humans and animals and the effects of toxins on ecology and the environment in terms of the risks on flora and fauna, with wider impacts on plant and food security. In particular the research will help to generate more valid models of toxicological processes that should permit confident, robust prediction of the effects of different dose levels which will in turn has the potential to offer enormous impact on the replacement, reduction and refinement of the use of animals in experiments, currently the main means of ascertaining such effects.
This research will improve methodologies applied within toxicology testing to improve the skills of those employed to perform analysis of safety and risk assessments associated with toxins. This will also promote the wider use of mathematical modelling within industries and groups associated with toxicology, offering the potential for wider employment and training opportunities in the relevant sectors for those with skills in the use and application of systems modelling.
This research has the potential to improve wealth creation in terms of the development of safer, more effective and efficacious drugs. It also has the potential to dramatically reduce the current costs required to support animal experimentation in safety testing through the mainstream application of more robust and valid modelling tools and techniques, replacing highly expensive experimentation. This has the potential for the creation of new companies to support modelling in toxicology and, through current relevant industrial sectors, enhance wealth creation within industries and agencies such as the pharmaceutical industry, the agricultural industry, water companies and providers and environment agencies.