OPTIMAL EXPERIMENT DESIGN IN POPULATION KINETICS

动力学分析和综合系统建模对我们理解药代动力学以及人类和动物代谢系统的生理学和病理生理学做出了重大贡献。动力学分析是一种每次检查一个主题的方法，目标是开发一个系统模型并使用该模型来解决特定的机械问题。种群动力学分析是在动力学研究中用于量化主体间变异性的方法。它被广泛应用于制药行业，因为它是了解药物在人群中的作用的关键。它越来越多地用于其他研究领域，在这些领域中，只有使用这些技术才能理解人口水平上的机械问题。与传统的动力学研究不同的是，在传统的动力学研究中，受试者数量很少，而种群动力学研究需要大量的受试者。特别是在制药行业，此类研究包括I期、II期和III期试验，其结果是获得FDA批准特定药物的关键，因此成本可能非常高。因此，以尽可能有效的方式设计人口研究，以节省资金，同时最大限度地利用数据所需的信息内容，是非常有意义的。近年来，改进种群动力学研究设计的方法受到了广泛的关注。临床试验模拟软件和最优抽样理论在种群动力学研究中的一些扩展正在研究中。然而，到目前为止，还没有协调一致的努力来评估各种方法并改进它们，以便能够产生帮助设计过程的软件工具。本提案将利用我们在种群动力学分析和最优抽样理论的理论和应用方面的独特专业知识来克服这一缺点，以(i)评估现有理论，（ii）开发软件工具来帮助种群研究设计。结果将是一套软件工具，这将有助于研究人员在该领域设计更有效的种群动力学研究。

Kinetic analysis and integrated systems modeling have contributed significantly to our understanding of pharmacokinetics, and of the physiology and pathophysiology of metabolic systems in humans and animals. Kinetic analysis is the methodology to examine one subject at a time, the goal being to develop a system model and use the model to address specific mechanistic questions. Population kinetics analysis is the methodology used to quantify intersubject variability in kinetic studies. It is widely used in the pharmaceutical industry since it is the key to understanding how drugs behave in a population. It is becoming increasingly used in other research areas where mechanistic questions at a population level can only be understood using these techniques. Unlike traditional kinetic studies where the number of subjects can be quite small, population kinetic studies require large numbers of subjects. Especially in the pharmaceutical industry where such studies comprise the Phase I, II and III trials, the results of which are key to obtaining FDA approval for a specific drug, the cost can be very large. It is therefore of great interest to design the population studies in the most efficient manner possible to save money while maximizing the information content required from the data. Methods to improve population kinetic study design have received a great deal of attention recently. Clinical trial simulation software and some extensions of optimal sampling theory to population kinetic studies are being investigated. To date, however, there has not been a concerted effort to assess the various methodologies and improve upon them so that software tools to aid in the design process can be produced. This proposal will overcome this shortcoming by taking advantage of our unique expertise in the theory and application of population kinetic analysis and optimal sampling theory to (i) assess existing theories and (ii) develop software tools to aid in population study design. The result will be a suite of software tools which will help researchers in the field design more efficient population kinetic studies.