Zanamivir - A review of clinical safety

Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neur aminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinica l studies completed up to the 17 July 1998 involving over 6000 adult and ad olescent patients from North America, Europe and the Southern Hemisphere. S erious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given f or both the treatment and prophylaxis of influenza-like illness. These find ings were independent of age and underlying medical condition. 4152 patient s received zanamivir and the most commonly reported adverse events were con sistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a seriou s adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmaco logy studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically si gnificant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tra ct irritancy at plasma exposures more than 100-fold higher than those antic ipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 1 97 times the current therapeutic dose (20 mg/day). The characteristics of t he molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intr avenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine a nd amantadine, as well as GS4104, a neuraminidase inhibitor currently in ph ase III development. This may be attributed to the low systemic bioavailabi lity of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a redu ced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver Therefore, the safety profile of zanamivir supports its use in the management of influenza .