Case Study 5 Clinical Receptor Theory Based Semimechanistic PD Model for the CCR5 Noncompetitive Antagonist Maraviroc

Maraviroc (UK-427 857), a selective and reversible CCR5 co-receptor antagonist, has been shown to be active in vitro against a wide range of clinical isolates [29]. In human immunodeficiency virus type 1 (HIV-1)-infected patients, maraviroc given as monotherapy for 10 days reduced HIV-1 viral load dose dependently by up to 1.6-log10 copies, consistent with currently available agents that comprise the cornerstone of highly active antiretroviral therapy. The objective of this study was to develop a novel combined viral dynamics/ operational model of (ant-)agonism that describes the PD effects of maravi-roc, a noncompetitive CCR5 inhibitor, on viral load. 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 effect of maraviroc was modeled using an inhibitory Emax model in the PD model acting on the infection rate constant of the virus and target cells. With this parameterization, it was assumed that the antagonistic effect of maraviroc is noncompetitive, which is consistent with recent in vitro findings. In terms of receptor theory and an operational model of drug action, the viral replication process was modeled as a binding-stimulus-response cascade in which the virus acts as an agonist, as shown in the five steps in Figure 8.

In the binding-stimulus-response cascade shown, Tmax is the maximum concentration of activated target cells that can be infected, V is the virus con-

Virus assembly

Figure 8 Viral dynamics-operational model (binding-stimulus-response). (From ref. 29, by permission of Wiley-Blackwell.)

Virus assembly

rsj -

[Tmax].[V]

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Project Management Made Easy

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