Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers

Objective: The objective of this study was to determine the sites of zanami vir deposition in the respiratory tract and the pharmacokinetics of zanamiv ir after oral inhalation from the Diskhaler(TM) device and from a prototype of a novel breath-activated device. Design: This was a 2-period block-randomised study in which participants in haled zanamivir from a Diskhaler(TM) and/or the prototype device on separat e 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 Tc-99m from the Diskhaler(TM) or the prototype device on separate day s. Scintigraphic images of the chest and oropharynx were recorded. Blood sa mples 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 lu ng function tests. A mean of 13.2% (n = 11) of the 10mg dose from the Diskh aler(TM) was deposited in the bronchi and lungs. The deposition pattern var ied between individuals, showing a preferentially central deposition patter n in some and a uniform distribution pattern in others. The major depositio n site was the oropharynx (mean 77.6%), with a mean of 1.2% deposited on th e trachea and a mean of 3.2% retained in the blister. Similar data were obt ained with the prototype device. Inhalation of zanamivir gave a broad peak of systemic absorption with mean maximum serum concentrations of approximat ely 30 to 40 mu g/L after 1.5 hours. The rate and extent of absorption were similar irrespective of inhalation device. Less than 5% of drug was excret ed unchanged in urine within 8 hours of inhalation, confirming the low bioa vailability of zanamivir after pulmonary delivery. A significant correlatio n existed between systemic exposure and peripheral lung deposition. Conclusions: The local concentrations of zanamivir that result from oral in halation via the Diskhaler(TM) are estimated to be >10 mu mol/L throughout the respiratory tract, well in excess of the concentrations observed to inh ibit influenza virus neuraminidases by 50% (0.64 to 7.9 nmol/L). Similar de position data were obtained with the Diskhaler(TM) and the prototype device , which was consequently not developed further. Pharmacoscintigraphy was co nfirmed as being a reliable technique for measuring zanamivir deposition in the respiratory tract.