Oseltamivir drug‐disease modelling in infants with influenza virus infection

Aims Oseltamivir is a commonly used neuraminidase inhibitor for treatment of influenza infection, but little data exist regarding concentration‐response relationships. Methods Pharmacokinetic (PK) and viral dynamic data from an earlier NIAID Collaborative Antiviral Study Group trial in paediatric patients with influenza from 0–23 months of age were used to create a PK model linked to an influenza viral dynamic model. Population PK parameters were used to perform broad dose‐ranging simulations to determine the oseltamivir carboxylate exposure required to achieve 95% of maximum viral suppression (EC 95 ). PK parameters of interest included the oseltamivir carboxylate steady‐state 12‐h area‐under‐the‐curve (AUC 12 ) and 12‐h trough concentration (C 12h ). AUC 12 and C 12h results were related to the time‐averaged area under the log 10 viral load‐time curve from Day 0 to Day 5 minus the baseline viral load (AAUCMB) using a maximum effect model. Results A total of 373 plasma samples for oseltamivir and 382 plasma samples for oseltamivir carboxylate from 78 infants were included. The median age and weight at the time of PK sampling were 8 months and 8 kg, respectively. Sixty‐two babies with measured influenza viral loads over the course of treatment (12 days, n = 239) were included in the viral dynamic modelling. The modelled EC 95 for AUC 12 and C 12h were 2710 ngxh/mL and 179 ng/mL, respectively. Conclusions Population pharmacokinetic modelling can be directly linked to viral dynamic outcomes and through simulations, dose‐ranging studies performed to identify target drug exposures. This approach could be used as a surrogate when concentration‐response data do not exist.