2. Academic Validation
  3. Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects

Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects

  • ACS Infect Dis. 2024 Aug 13. doi: 10.1021/acsinfecdis.4c00192.
Franziska Marwitz 1 2,  Gabriela Hädrich 3 4,  Natalja Redinger 5,  Karen F W Besecke 6 7 8,  Feng Li 3 4 9,  Nadine Aboutara 1 2,  Simone Thomsen 1,  Michaela Cohrs 4 10,  Paul Robert Neumann 4,  Henrike Lucas 4,  Julia Kollan 4,  Constantin Hozsa 6 7,  Robert K Gieseler 6 11,  Dominik Schwudke 1 2 12 13,  Marcus Furch 6 14,  Ulrich Schaible 2 5,  Lea Ann Dailey 3
Affiliations

Affiliations

  • 1 Bioanalytical Chemistry, Research Center Borstel, Leibniz Lung Center, Parkallee 1-40, Borstel 23845, Germany.
  • 2 German Center for Infection Research, Thematic Translational Unit Tuberculosis, Borstel 23845, Germany.
  • 3 Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2 ,Vienna 1090, Austria.
  • 4 Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 3, Halle/Saale 06120, Germany.
  • 5 Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, Parkallee 1-40 ,Borstel 23845, Germany.
  • 6 Rodos Biotarget GmbH, Feodor-Lynen-Straße 31, Hannover 30625, Germany.
  • 7 Siegfried Hameln GmbH, Langes Feld 13 ,Hameln 31789, Germany.
  • 8 Cardior Pharmaceuticals GmbH, Hollerithallee 20 ,Hannover 30419, Germany.
  • 9 Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Josef-Holaubek-Platz 2 ,Vienna 1090, Austria.
  • 10 General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460 ,Ghent 9000, Belgium.
  • 11 Department of Medicine, University Hospital, Knappschaftskrankenhaus Bochum, Ruhr University Bochum, In der Schornau 23-25 ,Bochum 44892, Germany.
  • 12 German Center for Lung Research (DZL), Airway Research Center North (ARCN), Research Center Borstel, Leibniz Lung Center, Borstel 23845, Germany.
  • 13 Kiel Nano, Surface and Interface Sciences (KiNSIS), Kiel University, Kiel 24118, Germany.
  • 14 Certmedica International GmbH, Magnolienweg 17 ,Aschaffenburg 63741, Germany.
PMID: 39136125 DOI: 10.1021/acsinfecdis.4c00192
Abstract

Liposomal formulations of Antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of ∼70 nm at a relatively high drug concentration (∼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type Lectin Receptors and mediate a preferential binding to macrophage Mannose Receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis Infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (∼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.

Keywords

bedaquiline; inhalation; liposomes; pharmacokinetics; tuberculosis.

Figures
Products