Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers.
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.
Steiner
Ilka
I
Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
Errhalt
Peter
P
Kubesch
Klaus
K
Hubner
Marianne
M
Holy
Marion
M
Bauer
Martin
M
Müller
Markus
M
Hinterberger
Sabine
S
Widmann
Rudolf
R
Mascher
Daniel
D
Freissmuth
Michael
M
Kneussl
Meinhard
M
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
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D018925:Chemokines; D016207:Cytokines; D010455:Peptides; C040522:duramycin