A mathematical analysis of rebound in a target-mediated drug disposition model. II. With feedback (Q2014347)

The authors investigate how receptor feedback influences the occurrence of rebound in the target-mediated drug disposition (TMDD) model. The receptor feedback is usually a dynamic process via some moderators; the TMDD model is modified to include feedback by adding an additional differential equation. In the case of very fast feedback, a quasi-equilibrium approach can be used and the feedback can be included in the synthesis term itself. The authors use the term ``direct feedback'' for the quasi-equilibrium approximation. The analysis of the TMDD model with the direct feedback approximation shows that the existence or non-existence of rebound is still linked to the elimination rates, though rebound can be expected in a larger region in the elimination parameter plane. It is shown that there is a similar region in the elimination rate plane as for basic TMDD model for which rebound will occur for any response speed. Furthermore, if the feedback responds slowly to a change in the receptor levels, the rebound will occur for any value of the elimination rates. The TMDD model is a one-compartment model, but the paper considers two classes of more general models with feedback (one class is related to multiple compartments, the other to more general feedback mechanisms) and shows that rebound will generically occur in such models for slow feedback moderator response. In the psoriasis example, it can be seen that the rebound can be significant, an increase of over 40. If the response of feedback goes to zero, then it is a case without feedback. Thus for many values of the elimination parameters the magnitude of the rebound will diminish if the response of the feedback slows down to zero and in the limit the rebound will have gone. In the paper, it is also shown that most of the results obtained on rebound in the model with slow feedback can be extended to more general systems of TMDD equations such as equations with more compartments. For Part I, see [the authors, ibid. 68, No. 6, 1453--1478 (2014; Zbl 1284.92037)].