OPTIMAL EXPERIMENT DESIGN IN POPULATION KINETICS

动力学分析和综合系统建模为我们理解人体和动物代谢系统的药代动力学、生理学和病理生理学做出了重要贡献。 动力学分析是一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。群体动力学分析是用于量化动力学研究中受试者间变异性的方法。 它被广泛用于制药行业，因为它是了解药物在人群中如何发挥作用的关键。它越来越多地用于其他研究领域，在人口水平上的机械问题只能使用这些技术来理解。与传统的动力学研究不同，受试者的数量可能很小，群体动力学研究需要大量的受试者。 特别是在制药行业，这些研究包括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，成本可能非常大。 因此，以尽可能有效的方式设计人口研究，以节省资金，同时最大限度地增加数据所需的信息内容，具有重大意义。近年来，种群动力学研究设计的改进方法受到了广泛的关注。 临床试验模拟软件和一些扩展的最佳抽样理论的人口动力学研究正在调查。 然而，到目前为止，还没有一个协调一致的努力，以评估各种方法，并改善他们，使软件工具，以帮助在设计过程中可以生产。 这项建议将克服这一缺点，利用我们独特的专业知识，在理论和应用的人口动力学分析和最佳抽样理论（i）评估现有的理论和（ii）开发软件工具，以帮助人口研究设计。 其结果将是一套软件工具，这将有助于该领域的研究人员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.