Structural Identifiability and Indistinguishability Analysis as Tools for Quantitative and Systems Pharmacology to Support the 3Rs

动物被广泛用于毒理学测试，以评估所检查过程对人类和环境的安全性和风险。据估计，欧洲每年有超过100万只动物被用于毒理学试验，其中约五分之一的动物被用于英国的毒理学试验。因此，主流使用有效、稳健的数学模型，可以比目前在实践中使用的模型更精确和更有信心地准确模拟此类试验的结果，显然将对未来所需的动物数量产生巨大影响，支持在毒理学测试实验中替代和减少动物的使用，并为动物福利提供阶级性变化。本提案旨在通过引入和应用已建立的和新颖的系统建模工具和技术，即结构可识别性和不可区分性分析，克服毒理学过程建模中存在的某些缺点。这些工具已被证明能够在参数估计和优化实验设计的信心方面提高模型的保真度。这些技术将应用于毒理学的范例问题，这将提供一个更强大的通用分析框架，以改善这些模型的参数估计、灵敏度、稳健性、可靠性和有效性。反过来，模型的这一步骤变化将加强实验设计，改进风险和安全评估，从而有助于支持动物使用的替代、减少和改进。这项研究将得到工业界（阿斯利康）的支持，并将应用于改善人类和动物安全的模型。这项工作将提供新的工具和种子出现一个新的领域，即定量和系统毒理学。

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.