A. Graphical presentation of the PK model of oseltamivir.

<p>Oseltamivir phosphate (OP) is absorbed at rate and converted into oseltamivir carboxylate (OC) at rate . OC is eliminated at rate . B. Graphical presentation of the viral kinetic symptom dynamic (VKSD) model with the effect of emerging resistance and oseltamivir therapy. Free virus infects target epithelial cells, which become infected cells not yet producing virus, and , which transition at rate into productively infected cells, and . These latter cells produce free virus and lead to the production of pro-inflammatory cytokines, either directly or via activation of macrophages or dendritic cells. Pro-inflammatory cytokines reduce the virus production rate, activate natural killer (NK) cells, and induce systemic symptoms. NK cells kill infected cells. Resistant virus can emerge during replication, infect target cells and induce the VKSD cycle. Oseltamivir acts by blocking the release of free viruses. is the target cell infection rate, is the transition rate from to , is the mortality rate of infected cells, is the effect of NK cells on infected cells, is the cytokine clearance, is the mortality rate of NK cells, is the rate of virus production by , is the effect of cytokines on , and is the virus clearance. , the initial number of target cells in the upper respiratory tract, was set to 4×10⁸. We set the cytokine and NK cell production rates to 1, as it changes only the units in which the early immune response is measured and does not lead to a loss of generality.