Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers

Objective: The objective of these studies was to examine the clinical pharm acokinetics and safety of zanamivir, an influenza A and B virus neuraminida se inhibitor, when administered to healthy volunteers. Design: The safety, tolerability and pharmacokinetics of zanamivir administ ered by a number of routes were assessed in randomised, double-blind and pl acebo-controlled studies. The study of absolute oral bioavailability had an open design. Study participants: The participants in these studies were healthy male or female volunteers. Interventions: Zanamivir was administered as single or multiple doses by th e intravenous, oral, inhaled (nebuliser and dry powder) and intranasal rout es. Serum and urine samples were obtained for determination of pharmacokine tic parameters, and nasal washes and throat gargles were performed to asses s drug concentrations in the nose and throat. Safety was evaluated by monit oring adverse events, vital signs and laboratory parameters. Results: Zanamivir was well tolerated at all doses by all routes; no seriou s adverse events were reported. The kinetics of zanamivir were linear with single intravenous doses up to 600mg, and there was no evidence of modifica tion in the kinetics after repeated twice-daily administration. Approximate ly 90% of zanamivir was excreted unchanged in the urine. The elimination of zanamivir from the serum was a first-order process with a half-life of app roximately 2 hours and, at 16L, the volume of distribution was similar to t hat of extracellular water. The absolute oral bioavailability of zanamivir was low, averaging 2%. After intranasal or oral inhaled administration, a m edian of 10 to 20% of the dose was systemically absorbed, with maximum seru m concentrations generally reached within 1 to 2 hours. The median serum ha lf-life ranged between 2.5 and 5.05 hours, suggesting that the elimination rate is limited by absorption. There was no evidence of modification in the kinetics after repeated inhaled administration. Conclusions: Zanamivir is a well tolerated drug. The low level of absorptio n of the drug after inhaled administration results in low serum concentrati ons, and therefore there is modest systemic exposure to zanamivir after inh alation. Zanamivir is not metabolised, and the potential for clinically rel evant drug-drug interactions is very low.