A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc.

AIM

To develop a novel combined viral dynamics/operational model of (ant-)agonism that describes the pharmacodynamic effects of maraviroc, a noncompetitive CCR5 inhibitor, on viral load.

METHODS

A common theoretical framework based on receptor theory and the operational model of (ant-)agonism has been developed to describe the binding of maraviroc to the CCR5 receptor and the subsequent decrease in viral load. The anchor point of the operational model in the differential equations of the viral dynamic model is the infection rate constant; this is assumed to be dependent on the number of free activated receptors on each target cell.

RESULTS

The new model provides one explanation for the apparent discrepancy between the in vivo binding of maraviroc to the CCR5 receptor (K(D) = 0.089 ng ml(-1)) and the estimated in vivo inhibition (IC(50) = 8 ng ml(-1)) of the infection rate. The estimated K(E) value of the operational model indicates that only 1.2% of free activated receptors are utilized to elicit 50% of the maximum infection rate.

CONCLUSIONS

The developed model suggests that the target cells, when activated, express more receptors (spare receptors) than needed. In the presence of maraviroc these spare receptors first require blocking before any decrease in the infection rate, and consequently in the viral load at equilibrium, can be detected. The model allows the simultaneous simulation of the binding of maraviroc to the CCR5 receptor and the change in viral load after both short- and long-term treatment.