Antifungal Efficacy,Safety, and Single-Dose Pharmacokinetics of LY303366, a Novel Echinocandin B,in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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Antifungal Efficacy,Safety, and Single-Dose Pharmacokinetics of LY303366, a Novel Echinocandin B,in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

Authors:	Vidmantas Petraitis Ruta Petraitiene Andreas H Groll Aaron Bell Diana P Callender Tin Sein Robert L Schaufele Carl L McMillian John Bacher Thomas J Walsh

Institution:	Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1. and Surgery Branch, Veterinary Resources Services, National Center for Research Resources,3. National Institutes of Health, Bethesda, Maryland, and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana2.

Abstract:	LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.The echinocandins are a new class of semisynthetic lipopeptide antifungal compounds, with potent and relatively broad-spectrum antifungal activity. They act by inhibiting the synthesis of (1,3)-β-d-glucan, an integral component of the fungal cell wall, resulting in cell wall damage and ultimately cell death (13, 15). The novel mode of action and potent antifungal activity in vitro have led to the design of several new compounds for potential clinical development.Cilofungin was the first echinocandin B derivative developed for clinical trials. This compound had excellent in vitro activity against Candida spp. and was highly effective in animal models of disseminated candidiasis (12–15, 28). The compound also showed activity in a murine model of disseminated aspergillosis (6, 29). However, clinical development of cilofungin was discontinued when toxicity due to the vehicle was observed.In recent years, a new generation of echinocandins has emerged. LY303366 (LY), a terphenyl-substituted echinocandin B, is the lead compound of this class for clinical investigation (4, 5, 10). Current in vitro studies demonstrate potent and non-cross-resistant antifungal activity against Candida albicans, Candida tropicalis, Candida glabrata, and other Candida species (7, 22, 30). The drug has also been shown to be active against Aspergillus spp. in vitro (20). Little is known, however, about the in vivo efficacy of LY against Aspergillus infections. Zeckner et al. (29) demonstrated improved survival and decreased tissue burden of Aspergillus fumigatus.Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in patients with persistent neutropenia (18, 24). The in vitro activity and preliminary in vivo antifungal effects in nonneutropenic mice suggest that LY may be an effective agent against this disease (16, 23, 29). Therefore, we investigated the antifungal efficacy and safety of LY in treatment and prophylaxis of primary pulmonary aspergillosis in persistently neutropenic rabbits.

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