title: Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits.
abstract: 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.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: V
authors.initials: V
authors.lastname: Petraitis
authors.forename: R
authors.initials: R
authors.lastname: Petraitiene
authors.forename: A H
authors.initials: AH
authors.lastname: Groll
authors.forename: A
authors.initials: A
authors.lastname: Bell
authors.forename: D P
authors.initials: DP
authors.lastname: Callender
authors.forename: T
authors.initials: T
authors.lastname: Sein
authors.forename: R L
authors.initials: RL
authors.lastname: Schaufele
authors.forename: C L
authors.initials: CL
authors.lastname: McMillian
authors.forename: J
authors.initials: J
authors.lastname: Bacher
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage; D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000517:prevention & control; D001232:Aspergillus fumigatus / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D005260:Female; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000517:prevention & control; D009503:Neutropenia / Q000150:complications* / Q000188:drug therapy* / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D010456:Peptides, Cyclic; D000666:Amphotericin B; D000077612:Anidulafungin