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.
