ABSTRACT
Developing novel compounds with low toxicity may present more difficulties for pharmaceutical companies than developing compounds with known class-related effects. The absence of clearly identified toxicity may be a consequence either of an inadequate or poorly designed toxicity programme or of the very low toxicity of the novel compound. To enable an informed risk assessment to be undertaken prior to registration, regulatory authorities must satisfy themselves that all efforts to fully evaluate the toxicity profile of a novel compound have been made. Zanamivir is a novel antiviral agent developed for the treatment and prevention of influenza when administered by the oral inhaled route. The toxicology programme for zanamivir was designed to support both a short term treatment indication for patients clinically diagnosed with influenza and a longer term treatment indication for the prevention of influenza. The toxicology studies demonstrated that zanamivir has very low toxicity and no drug-specific toxicities were observed in animal toxicity studies. Systemic plasma concentrations 1336-fold those achieved in clinical use were not associated with significant adverse effects. In the absence of dose-limiting toxicity in animal studies and in an attempt to identify target-organ toxicity, the high dosage level in all repeat dose studies was selected to be the maximum practicable. In the rat, nonspecific effects were seen in the respiratory tract following long term inhaled administration and in the kidneys following continuous infusion. However, these nonspecific effects were consequences of the excessive dosages administered and are not related specifically to zanamivir; thus, they are without relevance to the clinical use of this agent.
