The toxicity of moxifloxacin (BAY 12-8039), a novel fluoroquinolone with a broad spectrum of antibacterial activity, was evaluated in a comprehensive programme of toxicological studies that included single and multiple dose toxicity studies in rats, mice, dogs and monkeys, reproductive system toxicity studies in rats and monkeys and in-vitro and in-vivo mutagenicity assays. Although moxifloxacin is not intended for long-term clinical use, an accelerated bioassay in target organs to assess carcinogenesis was performed in rats. In addition to the routine toxicological programme required for the development of a drug intended for short-term administration, a major part of the preclinical programme for moxifloxacin comprised studies designed specifically to address the safety issues known to be features of fluoroquinolones, i.e. adverse effects on the central nervous and cardiovascular systems, phototoxicity, arthrotoxicity and oculotoxicity. The results of the toxicological investigations confirmed that the safety profile of moxifloxacin is comparable to those of other fluoroquinolones.
A study in young beagle dogs was performed in which the animals were treated for 2 weeks with ciprofloxacin at oral doses of 0, 10, 30 or 90 mg/kg per day. Immediately after treatment half of the number of animals were killed and all weight-bearing joints were subject to a thorough gross and histopathological investigation, including special staining of the cartilage matrix, and immunohistochemistry as well as electron microscopy. The remaining animals were maintained for an additional 5-months treatment-free period before being killed. Again, all weight-bearing joints were subject to a thorough gross and histopathological investigation. After 14 days of treatment with ciprofloxacin, oral doses of 30 and 90 mg/kg induced the characteristic arthropathy (blisters, erosions) in juvenile beagle dogs. As expected the lesions persisted while the animals were growing. In contrast, and to our knowledge demonstrated for the first time, an oral dose of 10 mg/kg ciprofloxacin did not induce joint lesions after short-term treatment in juvenile beagle dogs and was also not associated with arthrotoxicity when the dogs became older.
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