Zanamivir exposure in healthy rats and rats with acute lung injury.

OBJECTIVES: The aim of this study was to evaluate the pharmacokinetics and lung penetration of zanamivir in healthy rats and rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: Three pharmacokinetic (PK) studies have been conducted to evaluate systemic PK and local exposure of zanamivir in male Wistar rats (n = 62, 16 weeks old). Zanamivir was administered to healthy rats and rats with LPS-induced ALI intravenously (IV) and by inhalation (INH) via nebulisation. Serum and bronchoalveolar lavage (BAL) fluid concentrations were analysed to assess drug permeation across barriers. All zanamivir concentrations were determined using the HPLC-MS/MS method. RESULTS: The concentrations of zanamivir in BAL after IV dosing were approximately 3.1-, 4.0- and 5.0-fold higher in healthy animals compared with ALI at 30, 60 and 240 min after dosing, respectively (p = 0.005, 0.001 and 0.016). Zanamivir permeation between BAL fluid and serum was compared for IV and INH administrations, revealing that the BAL AUC(30-240) following IV administration was 6.5-fold lower than after INH. Furthermore, the AUC(30-240) in BAL fluid after IV administration was approximately 3.3 times higher in healthy animals than those with ALI (35,815 vs. 10,886 ng/mL × h). ALI also reduced the rate and extent of systemic absorption compared to healthy conditions. The absolute bioavailability of nebulised zanamivir was 1.91%. CONCLUSIONS: Our findings confirm PK superiority of INH administration to achieve local intrapulmonary exposition and indicate that ALI significantly impairs zanamivir penetration into the lungs from systemic circulation.