Indirect Link PK/PD Model

Direct link model is the most straight forward if there is no time delay between the plasma concentration and the response. However, this is not the case with most biologics. The indirect link model stipulates a separate effect site outside the central compartment, and the drug distribution to that compartment causes the delay of effect. Since no biologic example is available, diclofenac, a non-steroid anti- inflammatory is used to model the pain intensity response. When the effect compartment concentration is simulated from the plasma profile, the response is shown to directly correlated with the tissue (effect site) concentration.

The indirect link model differs from the direct link model by a separate, distinctive, effect compartment, as shown in the sketch The model assumes that drug concentration distributes to the effect site with a time delay, after which the drug concentrations between the tissue compartment and the central compartment are equilibrated. The delayed response is directly elicited by the drug concentration at the effect site, whose concentration is in equilibrium with the plasma compartment. By deduction, if an indirect model is observed, a distinctive effect compartment, a distribution lag and delayed response are implied.