Model-Building Strategies

Various strategies have been used when implementing whole body PBPK models. As discussed below, it is important to distinguish between model building for simulation from that for data analysis. In the latter case, parameter identifiability is a crucial element of the process. Debates on model structure are ongoing between the "complicators" (ie, those wishing to retain as much of the higher level structure of the global model as possible) and the "KISsers" (those wishing to "keep it [the model] as simple as possible," through lumping of various tissues together). Whatever the case, the modeling process and, implicitly the complexity of the model it- self, are best undertaken with an eye to the intended application. In practice, this may vary during drug discovery and development as more data become available (such as tissue levels obtained during safety assessment); hence, it is very important to be flexible in the approach. Moreover, if model reduction is employed, it should be undertaken in a formal and systematic way-rather than in the arbitrary manner so commonly seen-and it should allow for model expansion, if subsequently needed.

A parallel activity has been the development of models to describe the performance of individual organs and tissues of the body. In its simplest and commonly ap-plied form, each tissue is regarded as a well-stirred sys-tem, yet experimental data sometimes point to the need for more realistic yet more complex models that take into account such factors as the various physical spaces within tissues, the existence of permeability barriers, organ heterogeneity, and active transport or metabolic processes.