A PBPK model describing a xenobiotic with a short PK event scale

Physiologically-based pharmacokinetic (PBPK) modeling has been widely used in human risk assessment and in early drug development to predict human PK from in vitro and/or in vivo animal data. Recently, the application of PBPK modeling has been extended to the evaluation of drug-drug interactions. For most xenobiotic agents, the PK event scale such as elimination is in hours or days. This is much longer than the transit time of the agent in the body, and a PBPK model can be significantly simplified through lumping based on the physiochemical properties, mass transfer, and biotransformation. However, for a xenobiotic agent with a short PK event scale, e.g. in minutes, such an approach is not applicable. In this manuscript, the authors used the observed PK data from an ultrasound contrast agent to illustrate the role of a short PK event scale in the development of a suitable PBPK model. The model development process showed that a PBPK model assuming uniform venous and arterial blood pools, with a static lung model including alveolar and tissue regions, was unable to adequately capture the characteristics of the PK of the agent. Detailed information describing the pulmonary and cardiovascular circulation, and a heterogeneous dynamic lung model became necessary for the model. This exercise once again demonstrates the importance of the principles and methodologies that have been established since the 1960s that need to be followed during PBPK model development.