Naunyn-Schmiedebergs Archives of Pharmacology 2008-09-01

Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers.

Ilka Steiner, Peter Errhalt, Klaus Kubesch, Marianne Hubner, Marion Holy, Martin Bauer, Markus Müller, Sabine Hinterberger, Rudolf Widmann, Daniel Mascher, Michael Freissmuth, Meinhard Kneussl

Index: Naunyn Schmiedebergs Arch. Pharmacol. 378(3) , 323-33, (2008)

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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.