Population modelling of influenza viral kinetics, immune response, symptom dynamics and the effect of oseltamivir

Background: Oseltamivir is an oral prodrug indicated for the treatment and prophylaxis of influenza. However, there is a paucity of disease models that incorporate the time course of influenza infection with antiviral effects and host system dynamics. This information is critical to optimise dose selection and duration of treatment.
Objectives: To develop an influenza disease model that integrates the effect of oseltamivir on viral kinetics (VK), cytokine concentrations (IL-6) and clinical symptom score (CSS).
Methods: Human adult volunteers (Study PV15616) were inoculated with 106 PFU/mL influenza virus A/Texas (H1N1). Infected subjects (N = 69) were treated at 28 hours post-inoculation and received oral oseltamivir (20, 100, 200 mg BID or 200 mg QD) or placebo over five consecutive days. Serum and nasal swab samples were collected for the measurement of VK, oseltamivir and
IL-6 concentrations. A validated symptom severity scale was used to evaluate CSS twice-daily. The data were simultaneously fitted by nonlinear-mixed effects modelling using S-ADAPT and NONMEM.
Results: The time course of influenza A virus in nasal tissue was described using established VK disease models 1-4. This life-cycle was characterized by a 4-compartment model for virus (V), target epithelial (T), infected non-productive (I1) and infected productive (I2) cells. The pharmacodynamic effect of oseltamivir was to inhibit virion production from infected cells. The estimated EC50 was 104 ng/mL (between-subject variability, BSV 25%). A turnover model described the I2-induced increase in cytokine concentrations, with serum IL-6 stimulating the onset of CSS response. Following a peak, CSS returned towards baseline with a rate constant of 0.732 day-1.
Conclusions: An integrated disease model has been developed that relates the oseltamivir concentration-effect on influenza VK, host IL-6 modulation and CSS measures. This model serves as a basis for understanding influenza dynamics in the natural infection setting, and can be used to guide antiviral chemotherapy and assess new drug candidates.


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