Skip to 0 minutes and 15 seconds Now the complex response model. The response is mediated through the complex physiologic and regulatory pathways. The physiologic pathway involved the stimulation or inhibition of physiologic process. The regulatory pathway involves a molecular response mediator, such as hormone or cytokine. And the mix of these is a complex response model. It could include cell life span as well, or it could involve biofeedback mechanism, particularly for endogenous proteins. Or it involves tolerance of the drug or biologics. Let’s look at the complex response model. Here, this model involved the suppression and depression effect of LH-RH antagonist. In this model, you have the LH surge delay that is there’s a delay of the biologics to the effective compartment. Nevertheless, it stimulates LH secretion.
Skip to 1 minute and 47 seconds So this is an indirect link model because it involves a distributional delay of the biologics from the central compartment to the effect compartment. And it is the concentration in the effect compartment that elicits the pharmacological response. And there is a delay. Nevertheless, the response still happens because of the interaction of the biologics and the receptor. On the other hand, the LH suppression is an indirect response. It triggers a series of event that leads to the suppression of the LH hormone. So it does not involve the direct interaction of the biologics and receptor. So the combination of these two models the indirect response model and the indirect link model is the complex response model.
Skip to 3 minutes and 0 seconds Now the implications of PK/PD correlation, just as a summary. If the response time curve follows a direct link model, then we know the effect site is within the rapidly equilibrated central compartment
Skip to 3 minutes and 28 seconds If the response time follow the indirect link model, then we know there is a separate effect compartment and that there’s a distributional delay between the central compartment and the effect compartment for the biologics. And when we see a counter-clockwise hysteresis, it could be an indirect link model. Now if the indirect response model, it involves a cascade of events that lead to the response. Clotting factor would be a typical example. There is a series of biochemical events that lead to the clotting of blood that’s indirect response. Cell life span model. That’s a very specific mechanism that are involved, as I mentioned earlier, involved in erythropoiesis, in the granulopoiesis, and thrombopoiesis.
Skip to 4 minutes and 43 seconds And the complex response model is the combination of two or more of the four models or the time-dependent pathways. For example, the stimulation first and then suppression later. That’s a complex response model. So this part concludes the PK/PD correlations and their implications for drug action or biological action and the biologics action mechanism. So I hope that you’ll be able to take home some important information and the knowledge that you can apply in the future in your research work.
Complex Response Model
By definition, a complex response model implies the involvement of complex physiologic and regulatory pathways. Logically, the model could be a combination of 2 or more existing models, with biofeedback mechanism, physiological tolerance or other attributes. These five models form a Model-Based Drug Development paradigm which has been used as a strategy for improving pharmaceutical R&D productivity.
The last model to be discussed in this section is the complex response model By definition, the model implies the involvement of complex physiologic and regulatory pathways. The physiologic pathway could include stimulation or inhibition of physiologic process, for example, the suppression and stimulation effect of LH-RH antagonist Regulatory pathway could involve molecular response mediators such as hormones or cytokines. In addition, the model could be a combination of 2 or more existing models, with biofeedback or physiological tolerance. The implications of PK/PD modeling is recaptured in a brief review.