Indirect Response Model and Cell Life Span Model

The distinctive characteristics of an indirect response model is that the response is not triggered by an interaction of drug with receptor. Rather, it is elicited via a response mediator, which is formed through a defined transduction process. The time course of plasma concentration and effect are dissociated, resulting in a delay of response and possible counter-clockwise hysteresis. For cell life span model, therapeutic proteins elicit response through direct or indirect modulation of special blood or immune cell types.

In the indirect response model, the response is delayed, as in the indirect link model but for different reasons. This is not due to a delay in drug distribution but the formation of a response mediator. A notable example is warfarin’s role in the coagulation cascade, which leads to reduced production of fibrin. Another example involved an rh-MAb that displays a similar pattern. The MAb suppressed eosinophil count by binding with IL-5 and deactivate its signaling capacity. Cell life span model is based on a certain set of specific mechanisms. For example, rh-EPO effect is modeled as stimulation of the maturation of two erythrocytic precursors and reticulocytes. Life cell span model is suited for characterizing the conc (dose)-response relationship of erythropoiesis, granulopoiesis and thrombopoiesis.