摘要：

Objective The objective of this study was to determine the sites of zanamivir deposition in the respiratory tract and the pharmacokinetics of zanamivir after oral inhalation from the Diskhaler device and from a prototype of a novel breath-activated device. Design This was a 2-period block-randomised study in which participants inhaled zanamivir from a Diskhaler and/or the prototype device on separate days. Study participants 13 healthy volunteers (5 men and 8 women) aged 20 to 42 years (mean age 29 years) and weighing 54.0 to 94.0kg (mean bodyweight 69.2kg) entered the study. Interventions Participants were given dry powder zanamivir 10mg formulated with 99m Tc from the Diskhaler or the prototype device on separate days. Scintigraphic images of the chest and oropharynx were recorded. Blood samples for determination of serum zanamivir and urine for excretion studies were taken up to 8 hours after drug administration. Safety was evaluated by monitoring lung function tests, adverse events and laboratory parameters. Results Orally inhaled zanamivir was well tolerated, as demonstrated by lung function tests. A mean of 13.2% (n = 11) of the 10mg dose from the Diskhaler was deposited in the bronchi and lungs. The deposition pattern varied between individuals, showing a preferentially central deposition pattern in some and a uniform distribution pattern in others. The major deposition site was the oropharynx (mean 77.6%), with a mean of 1.2% deposited on the trachea and a mean of 3.2% retained in the blister. Similar data were obtained with the prototype device. Inhalation of zanamivir gave a broad peak of systemic absorption with mean maximum serum concentrations of approximately 30 to 40 μg/L after 1.5 hours. The rate and extent of absorption were similar irrespective of inhalation device. Less than 5% of drug was excreted unchanged in urine within 8 hours of inhalation, confirming the low bioavailability of zanamivir after pulmonary delivery. A significant correlation existed between systemic exposure and peripheral lung deposition. Conclusions The local concentrations of zanamivir that result from oral inhalation via the Diskhaler are estimated to be > 10 μmol/L throughout the respiratory tract, well in excess of the concentrations observed to inhibit influenza virus neuraminidases by 50% (0.64 to 7.9 nmol/L). Similar deposition data were obtained with the Diskhaler and the prototype device, which was consequently not developed further. Pharmacoscintigraphy was confirmed as being a reliable technique for measuring zanamivir deposition in the respiratory tract.

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