Physiologically based models: Techniques and applications to drug delivery

Physiologically based pharmacokinetic (PBPK) models allow integrated representations of the time course of drug concentrations in the important organs and sites of drug action, toxicity, absorption, metabolism, and excretion. PBPK models have multiple compartments representing defined organs or physiological spaces, with parameters that are potentially directly measurable. They lie on a continuum of pharmacokinetic model types, which includes Compartmental (least complex), Semi-PBPK, PBPK, and Systems Biology (most complex) models. Compartmental models are typically parameterized using a “top-down” approach, where the model is fitted to a specific data set to estimate parameter values. PBPK models are typically parameterized using a “bottom-up” approach, where model parameters are derived from literature, in vitro data, or scaled data from another species. Although there is increasing availability and use of commercial software for PBPK modeling, it is feasible to construct bespoke PBPK for specific projects using general-purpose software platforms. The challenge here is often collecting, collating, and justifying the data used to parameterize the model. In this chapter, the fundamental equations for a simple PBPK models are presented with respect to key “submodels” of an example whole-body model. The current rise in the rate of publication and application of PBPK models is likely to be sustained in the foreseeable future. Contributing factors will likely be the wider use of commercial PBPK models, the advent of broader collective efforts to advance and coordinate PBPK and Systems Biology modeling, and the increasing ease with which bespoke PBPK models can be coded and shared.