title: Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults.
abstract: Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC(0-tau)) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC(0-tau) in plasma. The mean (standard deviation) half-life and AUC(0-tau) were 6.9 (2.1) h and 39.5 (19.8) microg h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) microg h/ml, respectively, for anidulafungin. The AUC(0-tau) values for ELF and AM were 282 and 178 microg h/ml, respectively, for voriconazole, and 21.9 and 1,430 microg h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC(90)/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Banevicius
authors.forename: Annie F
authors.initials: AF
authors.lastname: Fang
authors.forename: Penelope H
authors.initials: PH
authors.lastname: Crownover
authors.forename: R Fredrick
authors.initials: RF
authors.lastname: Knauft
authors.forename: J Samuel
authors.initials: JS
authors.lastname: Pope
authors.forename: John H
authors.initials: JH
authors.lastname: Russomanno
authors.forename: Eric
authors.initials: E
authors.lastname: Shore
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
mesh_terms: D000328:Adult; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D011743:Pyrimidines; D014230:Triazoles; D000077612:Anidulafungin; D065819:Voriconazole