A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Abstract

A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate ␤, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate ␦, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (␤) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation. O seltamivir is an orally active antiviral which inhibits the neuraminidase enzyme necessary for the release of newly replicated influenza virus from infected cells. Oseltamivir has a wide spectrum of activity, acting against a range of influenza A and B subtypes. The Centers for Disease Control and Prevention reported that 99.6% of the 2009 H1N1 viral strains tested were susceptible to oseltamivir (see http://www.cdc.gov/H1N1flu /recommendations.htm). The standard regimen of 75 mg twice a day (b.i.d.) for 5 days is used for treatment of seasonal influenza as previous studies in adult subjects showed that this regimen results in plasma levels sufficient to inhibit neuraminidase enzyme activity from all the tested seasonal influenza virus strains (1, 2). The same treatment regimen was applied in the most recent H1N1 pandemic in 2009-2010 without a prospective dose optimization trial, due to the impracticality of performing such a study on an emergent viral strain during a pandemic. The World Health Organization has recommended use of higher doses (150-mg regimen) for treatment of highly virulent strains such as H5N1 (3). In addition, there were reported concerns regarding the ability of oseltamivir manufacturing capacity to fully meet global stockpiling demands if a rapid pandemic ensues (4, 5). This factor, in addition to opportunities for enh...

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