PK/PD-based adaptive tailoring of oseltamivir doses to treat within-host influenza viral infections.

Abstract

Influenza A virus (IAV) is a latent global threat to human health. In view of the risk of pandemics, prophylactic and curative treatments are essential. Oseltamivir is a neuraminidase inhibitor efficiently supporting recovery from influenza infections. Current common clinical practice is a constant drug dose (75 or 150 mg) administered at regular time intervals twice a day. We aim to use quantitative systems pharmacology to propose an efficient adaptive drug scheduling. We combined the mathematical model for IAV infections validated by murine data, which captures the viral dynamics and the dynamics of the immune host response, with a pharmacokinetic (PK)/pharmacodynamic (PD) model of oseltamivir. Next, we applied an adaptive impulsive feedback control method to systematically calculate the adaptive dose of oseltamivir in dependence on the viral load and the number of immune effectors at the time of drug administration. Our in silico results revealed that the treatment with adaptive control-based drug scheduling is able to either increase the drug virological efficacy or reduce the drug dose while keeping the same virological efficacy. Thus, adaptive adjustment of the drug dose would reduce not only the potential side effects but also the amount of stored oseltamivir required for the prevention of outbreaks.