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Skip to 0 minutes and 14 seconds Now let’s look at the indirect response model. This is the third PK/PD model that we want to talk about. Now, the effect or the response of many therapeutic proteins is not mediated via direct interaction of drug and receptor, which is the basis for the direct link and indirect link model. That is, the response is elicited by the interaction of the biologics and receptor. But that is not the case for many therapeutic proteins. Instead, the response is elicited through the formation of a response mediator. And the response mediator is formed through a transduction process, that either stimulates or inhibits a physiologic function or synthesis or degradation of a hormone or cytokine.

Skip to 1 minute and 21 seconds Therefore, the time course of plasma concentration and the effect are really or actually dissociative, resulting in counterclockwise hysteresis. So indirect response model also results in counterclockwise hysteresis. But it is not a distributional delay is not due to a distributional delay or is not tolerance. Let’s look at the indirect response. Here is plasma concentration for a monoclonal antibody which suppresses eosinophil count. The plasma concentration peak at about 2 days after administration. when you look at eosinophil count, the depression or the suppression did not happen until about 18 days later. So plasma peaks at 2 days. The effect peaks at or on day 18. So this is indirect response. Here is the model for indirect response.

Skip to 2 minutes and 49 seconds Again you have the drug or biologics injected intravenously into the central compartment

Skip to 2 minutes and 59 seconds which then increase or synthesis. Or decrease or degradation of the response mediate.

Skip to 3 minutes and 20 seconds Then that result is the effect. So this is the indirect response model. That works through a response mediator is not the direct interaction of biologics with the receptor.

Skip to 3 minutes and 40 seconds Now cell life span model is an entirely different mechanism. In this case, the therapeutic proteins actually elicited response through direct or indirect modulation of blood or immune cell types. the rhEPO effect is typical of this. The erythropoietic effect was modeled as stimulation of the maturation of two progenitor cell populations. Eventually leading to the production of red blood cells. And because of this type of model, it takes longer or it takes weeks to observe for example the erythropoietic effect. And this model is used for characterizing the concentration-response or dose-response relationship for erythropoietic, for granulopoiesis for thrombopoiesis.

Skip to 4 minutes and 58 seconds Let’s look at the process of erythropoiesis. Bone marrow, where the erythropoietin stimuli to produce the red blood cells and eventually secreted into the blood.

Skip to 5 minutes and 17 seconds And the process involved 4 steps: the P1 takes about 3 to 4 days, P2 takes about up to 48 hours, and then another step, another two steps altogether it takes about 120 days. For the red blood cell to be produced and secreted into circulation.

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.

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Pharmacotherapy: Understanding Biotechnology Products

Taipei Medical University