Figure 4.

Model structure of multiscale PBPK–PD–signal transduction (ST) application example. The figure outlines the most relevant processes captured in the multiscale model. Details (e.g., additional organs, sub-compartments, and proteins) are omitted for clarity. A whole-body PBPK model is constructed for a prodrug and its active metabolite. The two substances are coupled via a hepatic CYP2D6 clearance of the prodrug, which is the source for the active metabolite. A tumor (PD) model is contained in the pancreas of the whole-body model, considering resting, dividing, and dead cell populations. Within the resting cells an EGFR signal transduction model is nested. Raf, a kinase participating in the signal transduction process, is the target of the active metabolite. ERKPP, a transcription factor, drives the transition into the dividing population. The sum of resting and dividing cells constitutes the viable tumor mass and serves as a primary output. For additional details, see Materials and Methods.