Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development.

译文

药物开发是一个复杂、漫长和昂贵的过程。制药公司和监管机构已经认识到,鉴于投资回报,药物开发过程需要优化效率。药代动力学和药效学是决定剂量和反应之间关系的两个主要原则。本文通过将药代动力学,药效学和疾病方面联系到数学模型中,提供了有关药物开发综合方法的最新信息。逐渐地,正在从相当经验的方法过渡到基于建模和模拟的药物开发方法。主要学习阶段应该是0、I和II阶段,而III阶段研究应该只是具有确认性目的。在基于模型的药物开发中,沿着开发路径迭代完善的基于机制的数学模型结合了研究药物,疾病及其在目标人群的不同子集中的相互干扰的积累知识。这些模型有助于下一项研究的设计,并提高实现预期疗效和安全性终点的可能性。在本文中,讨论了药物开发综合方法的几个理论和实践方面,以及来自不同治疗领域的一些案例研究,说明了药代动力学/药效学疾病模型在药物开发的不同阶段的应用。

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