title: Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers.
abstract: Duramycin (Moli1901) is being developed for the treatment of reduced mucociliary clearance in cystic fibrosis. This study was conducted to estimate lung residence time and systemic exposure and to assess whether duramycin causes an inflammatory response. Six volunteers were administered a single dose (7.5 mg) of nebulized duramycin and underwent bronchoscopies to obtain a composite data set for pharmacokinetic analysis; duramycin was measured in the cellular fraction of bronchoalveolar lavage fluid (BALF) (mainly alveolar macrophages) and brush biopsies (bronchial epithelial cells). The estimated t(1/2) of duramycin was approximately 5 days in brush biopsies and 25 to 91 days in BALF cells. Levels of duramycin in BALF (C (max) 800 ng/mg) exceeded those in brush biopsies by approximately 20-fold. Duramycin was absent from plasma and did not cause any detectable inflammatory response in pulmonary tissue as judged from the BALF profile of 14 relevant cytokines. Our data suggest that duramycin qualifies for intrapulmonary administration in cystic fibrosis (CF) patients.
authors.affiliation: Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ilka
authors.initials: I
authors.lastname: Steiner
authors.forename: Peter
authors.initials: P
authors.lastname: Errhalt
authors.forename: Klaus
authors.initials: K
authors.lastname: Kubesch
authors.forename: Marianne
authors.initials: M
authors.lastname: Hubner
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Sabine
authors.initials: S
authors.lastname: Hinterberger
authors.forename: Rudolf
authors.initials: R
authors.lastname: Widmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Mascher
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.forename: Meinhard
authors.initials: M
authors.lastname: Kneussl
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001430:Bacteriocins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001999:Bronchoscopy; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009330:Nebulizers and Vaporizers; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D018925:Chemokines; D016207:Cytokines; D010455:Peptides; C040522:duramycin