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[S4] -

[S3]

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

centration, Kv is the theoretical concentration of viruses that elicits half the maximum binding to the activated receptors on the target cells, and Kex is the theoretical stimulus (SX) at step X that elicits half the maximum response (SX+1) at step X + 1 (X = 1to5). This new model provided an explanation for the apparent discrepancy between the in vivo binding of maraviroc to the CCR5 receptor (KD = 0.089 ng/mL) and the estimated in vivo inhibition (IC50 = 8 ng/mL) of the infection rate. The estimated KE value of the operational model indicates that only 1.2% of free activated receptors are utilized to elicit 50% of the maximum infection rate. The model developed 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 allowed 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. The current model will be used to guide the selection of the optimal dosage regimen for maraviroc in HIV-1-infected patients.

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Project Management Made Easy

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