An introduction to physiologically-based pharmacokinetic models

Physiologically-based pharmacokinetic (PBPK) models represent drug kinetics in one or more 'real' organs (and hence require submodels of organs/tissues) and they describe 'whole-body' kinetics by joining together submodels with drug transport by blood flow as dictated by anatomy. They attempt to reproduce 'measureable' physiological and/or pharmacokinetic processes rather than more abstract rate constants and volumes. PBPK models may be built using a 'bottom-up' approach, where parameters are chosen from first principles, literature, or in vitro data as opposed to a 'top-down' approach, where all parameters are estimated from data. The basic principles of PBPK models are described, focusing on the equations for three individual organs: a single flow-limited compartment describing distribution only, a membrane-limited compartment describing distribution, and a single flow-limited compartment with elimination. These organ models are linked to make a basic three-compartment physiological model of the whole body. PBPK models are particularly suited to scaling kinetics across body size (e.g., adult to neonate) and species (e.g., animal to first-in-man) as physiology and pharmacology can be represented by independent parameters. Maturation models can be incorporated as for compartmental models. PBPK models are now available in commercial software packages, and are perhaps now more accessible than ever. Alternatively, even complex PBPK models can be represented in generic differential equation-solving software using the simple principles described here. The relative ease of constructing the code for PBPK models belies the most difficult aspect of their implementation-collecting, collating, and justifying the data used to parameterize the model.