T-8581, a new orally and parenterally active triazole antifungal agent: In vitro and in vivo evaluations

Abstract

T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80s; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 μg/ml; fluconazole, 0.148 μg/ml; and itraconazole, 0.0170 μg/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T- 8581, 9.28 μg/ml; fluconazole, 4.00 μg/ml; and itraconazole, 0.119 μg/ml. For Aspergillus fumigatus the GM-IC80s were as follows; T-8581, 71.0 μg/ml; fluconazole, 239 μg/ml; and itraconazole, 0.379 μg/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and >320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, and >320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was >20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits, and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.