LY303366 is a novel semisynthetic derivative of
echinocandin B and a potent inhibitor of fungal
(1,3)-beta-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.