[Nonclinical studies and clinical studies on fosfluconazole, a triazole antifungal agent (Prodif)]

Fosfluconazole is a phosphate prodrug of fluconazole that has been developed to reduce the volume of fluid required to administer fluconazole by the intravenous route. Fosfluconazole is hydrolyzed by alkaline phosphatase to fluconazole and phosphoric acid. Fosfluconazole had no significant antifungal activity in vitro. However, in rat models of acute systemic candidiasis and intracranial cryptococcosis, fosfluconazole retained the antifungal potency and efficacy of fluconazole. This reflects the effective conversion of the prodrug to the parent during the course of the experiments. The 2-day-loading dose regimen led to earlier achievement of target fluconazole steady state plasma concentrations compared to use of the 1-day- or no-loading dose regimen of fosfluconazole. The efficacy and safety of fosfluconazole were investigated with the 2-day-loading dose regimen in patients with deep-seated mycosis caused by Candida and Cryptococcus species. The efficacy rates were 73.8% in the domestic Phase III study and 91.7% in the foreign Phase III study. Adverse events were observed in 31 cases (19.4%) out of 160 in both studies. These results indicate that fosfluconazole is effective for the treatment of deep-seated mycosis and shows no clinically significant adverse events in the Phase III studies