New azole compounds: vibunazole (Bay n7133) and Bay ℓ9139, compared with ketoconazole in the therapy of systemic candidosis and in pharmacokinetic studies, in mice

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Abstract
Ketoconazole, a new imidazole: Bay ℓ9139, and a new triazole: vibunazole (Bay n7133) were compared in therapy of systemic candidosis. CD-I male mice were challenged with Candida albicans intravenously (>LD80), and treated twice a ay, orally, for one month. The isolate of Can. albicans used, and isolates obtained after treatment with the antifungals, were susceptible to all three drugs (MICs ≤ 0.5mg/l). No drug was lethal to uninfected mice in doses of 200 mg/kg/day for one month. With therapy started on the day after infection, all three drugs at 50 or 100 mg/kg/day prolonged survival, compared with controls (P≤0.05), with ketoconazole slightly superior to the other two drugs, but none id so at 25 mg/kg/day. At 200 mg/kg/day ketoconazole and vibunazole were protective, but ℓ9139 was not, and this suggested synergistic toxicity of ℓ9139 with Can. albicans infection, at this dose. With treatment begun on day 4, ketoconazole prolonged survival (P≤0.005) at 200 or 100 mg/kg/day compared with controls, but ketoconazole at 10–50 mg/kg/day, and vibunazole and ℓ9139 at 10–200 mg/kg/day were ineffective. Survivors had renal lesions and cultureproven esidual infection. Pharmacokinetic studies indicated lower peak vibunazole and 9139 serum concentrations, and reduced area-under-curve (AUC), after 26 days of treatment, as against single dose administration. The relative inemcacy of vibunazole and ℓ9139 appears to be related to unfavourable pharmacokinetic properties with continued administration.