Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administered ravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits.
Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.
Petraitiene
Ruta
R
Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Petraitis
Vidmantas
V
Lyman
Caron A
CA
Groll
Andreas H
AH
Mickiene
Diana
D
Peter
Joanne
J
Bacher
John
J
Roussillon
Kristin
K
Hemmings
Melissa
M
Armstrong
Derrek
D
Avila
Nilo A
NA
Walsh
Thomas J
TJ
D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D006207:Half-Life; D007091:Image Processing, Computer-Assisted; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007275:Injections, Intravenous; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008351:Mannans / Q000097:blood; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications*; D011817:Rabbits; D016019:Survival Analysis; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D008351:Mannans; D013778:Tetrazolium Salts; D013844:Thiazoles; D014230:Triazoles; C012990:galactomannan; D000666:Amphotericin B; C104066:ER 30346; C022616:thiazolyl blue; D005690:Galactose