Sahota Tarjinder, Danhof Meindert, Della Pasqua Oscar
Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands.
Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands, Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, Uxbridge, UK, Clinical Pharmacology and Therapeutics, University College London, London, UK
Mutagenesis. 2016 May;31(3):359-74. doi: 10.1093/mutage/gev081. Epub 2016 Mar 12.
Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits can be anticipated for the assessment of safety and toxicity profile of novel molecules.
尽管人们一直在努力更好地理解安全性和毒性背后的机制，但在药物研发过程中，仍有30%的淘汰是由于安全问题。需要改变当前安全性和毒性评估的做法，以减少后期淘汰率，并推动新型药物的有效开发。本综述重点关注经验证据生成对药物研发过程中安全性和毒性评估的影响。需要转变范式，以（i）确保将药理学概念纳入安全性和毒性评估；（ii）促进历史证据的整合，从而实现跨物种以及体外和体内实验结果的转化；（iii）推动使用针对特定安全性和毒性问题量身定制的实验方案。基于历史实例，我们强调了新分子安全性概况早期表征面临的挑战，并讨论了基于模型的方法如何应用于实验方案的设计和分析。与科学原理相关的问题被分类并呈现为描述决策过程的层次树。重点关注四个不同领域，即优化、转化、分析构建和决策标准。从方法学角度，结合群体和贝叶斯建模技术（如非线性混合效应建模）的进展，讨论了毒理学和安全药理学实验方案中用于风险估计和外推的定量方法（如起始点和效力）的相关性。它们在药代动力学（PK）和药代动力学-药效学关系（PKPD）评估中的应用，使人们对人类药物的剂量原理在疗效和不良事件方面有了更深入的了解。预计在新型分子安全性和毒性概况评估中也会有类似的益处。
