Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers (original) (raw)

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 t1/2 of duramycin was ∼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 ∼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.

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Acknowledgements

This work was supported by grants from AOP Austrian Orphan Pharmaceuticals AG. IS is supported by a fellowship from the Main Association of Austrian Social Security Institutions

The clinical study protocol for the present work was provided by AOP Orphan Pharmaceuticals AG. We are grateful to Dr. Christian Joukhadar, former employee of the Medical University Vienna, for his contribution as “Prüfer” according to Austrian drug law. IS is supported by a fellowship from the Austrian Federation of Social Security Institutions.

Disclosure

RW is CEO and SH is Head of the Clinical Department of AOP. They therefore have a financial interest. All other authors do not have any financial interest in this work, which is tied to the outcome of this study or to the performance of AOP. The work by IS, PE, MHu, MHo, MB, MM, MF, and MK was supported by a grant from AOP. The analytical work of KK and DM was reimbursed by AOP.

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Authors and Affiliations

1. Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringer Straße 13a, A-1090, Vienna, Austria
   Ilka Steiner, Marion Holy & Michael Freissmuth
2. Department of Pneumology, Wilhelminenspital der Stadt Wien, Montleartstrasse 37, A-1160, Vienna, Austria
   Peter Errhalt, Marianne Hubner & Meinhard Kneussl
3. Pharm-analyt Labor GmbH, Ferdinand-Pichler-Gasse 2, A-2500, Baden, Austria
   Klaus Kubesch & Daniel Mascher
4. Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
   Ilka Steiner, Martin Bauer & Markus Müller
5. AOP Orphan Pharmaceuticals AG, Wilhelminenstraße 91/II f/B4, A-1160, Wien, Austria
   Sabine Hinterberger & Rudolf Widmann

Authors

1. Ilka Steiner
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2. Peter Errhalt
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3. Klaus Kubesch
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4. Marianne Hubner
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5. Marion Holy
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6. Martin Bauer
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7. Markus Müller
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8. Sabine Hinterberger
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9. Rudolf Widmann
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10. Daniel Mascher
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11. Michael Freissmuth
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12. Meinhard Kneussl
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Correspondence toMichael Freissmuth.

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Steiner, I., Errhalt, P., Kubesch, K. et al. Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers.Naunyn-Schmied Arch Pharmacol 378, 323–333 (2008). https://doi.org/10.1007/s00210-008-0293-8

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• Received: 31 January 2008
• Accepted: 31 March 2008
• Published: 24 May 2008
• Issue Date: September 2008
• DOI: https://doi.org/10.1007/s00210-008-0293-8

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