Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
Clin Pharmacokinet. 2011 Aug;50(8):483-91. doi: 10.2165/11592400-000000000-00000.
Although clinical drug trials are indispensable in providing an appropriate background for dosage recommendations, they can provide mechanistic pharmacokinetic information only indirectly with the help of certain biomarkers for pathological, physiological and pharmacological determinants. Thus, to provide such mechanistic information of clinical value, various in vitro and in silico tests and approaches are increasingly employed in drug discovery and development. Integration of the results of these primarily preclinical studies has been made possible by various computational models, such as in vitro-in vivo extrapolation of hepatic clearance or physiologically based pharmacokinetic modelling. In this article, the current status of these modelling approaches is surveyed and some examples are given, highlighting advantages and disadvantages in applying them at various phases of drug development. A new paradigm of model-based drug development is briefly described, and the importance of the approach of integrating all of the information coming from different investigations at all levels--be it in vivo, in vitro or in silico--is emphasized.
虽然临床药物试验对于提供剂量建议的适当背景是不可或缺的，但它们只能借助某些生物标志物，间接地提供病理、生理和药理决定因素的药代动力学信息。因此，为了提供具有临床价值的这种机制信息，药物发现和开发中越来越多地使用各种体外和计算方法和方法。这些主要的临床前研究的结果的整合已经通过各种计算模型来实现，例如肝清除率的体外-体内外推或基于生理学的药代动力学建模。本文调查了这些建模方法的现状，并给出了一些例子，突出了在药物开发的各个阶段应用它们的优缺点。简要描述了基于模型的药物开发的新范例，并强调了整合来自不同水平的所有信息的方法的重要性，无论是在体内、体外还是在计算机上。
