Fig. 5.

Basic components of systems pharmacokinetic/pharmacodynamic models of genomic drug action. The PK is reflected by the concentration of drug in the central (plasma) compartment and its distribution to the effect site(s) in tissues. Local concentrations of unbound drug bind with free receptors that are synthesized (k_syn) and degraded (k_deg) over time in tissues. Target engagement and occupancy serves as the driving force for the inhibition and/or stimulation of the production (k_in) or removal (k_out) of multiple target gene biomarkers. Genomic markers and mediators of both therapeutic and adverse drug effects signal through interconnected gene (mRNA and protein) networks to mediate clinically measurable PD end-point responses. For drugs with genomic mechanisms, such as corticosteroids, signaling proteins related to efficacy and toxicity often do not transduce in a linear manner but interact through intertwined signaling networks.