title: Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis.
abstract: We studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of Aspergillus fumigatus inoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40- and ISA60-treated rabbits in comparison to those of UC (P < 0.001). ISA20-treated (P < 0.05), ISA40-treated, and ISA60-treated (P < 0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40- and ISA60-treated animals demonstrated a significant decline of serum (1→3)-β-d-glucan levels (P < 0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P < 0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40- and ISA60-treated rabbits (P < 0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1→3)-β-d-glucan levels.
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA vip2007@med.cornell.edu thw2003@med.cornell.edu.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
authors.forename: Patriss W
authors.initials: PW
authors.lastname: Moradi
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
authors.forename: Gittel E
authors.initials: GE
authors.lastname: Strauss
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Katragkou
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kovanda
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Transplantation-Oncology Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA Departments of Pediatrics and Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, New York, USA vip2007@med.cornell.edu thw2003@med.cornell.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000472:pathogenicity; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008351:Mannans / Q000627:therapeutic use; D009570:Nitriles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D008351:Mannans; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C012990:galactomannan; C508735:isavuconazole; D005690:Galactose