2. Academic Validation
  3. A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles

A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles

  • ACS Pharmacol Transl Sci. 2024 Nov 9;7(12):4123-4134. doi: 10.1021/acsptsci.4c00558.
Feng Li 1 2 3,  Franziska Marwitz 4 5,  David Rudolph 6,  Wiebke Gauda 4,  Michaela Cohrs 7,  Paul Robert Neumann 2,  Henrike Lucas 2,  Julia Kollan 2,  Ammar Tahir 8,  Dominik Schwudke 4 5 9 10,  Claus Feldmann 6,  Gabriela Hädrich 1 2,  Lea Ann Dailey 1 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
  • 2 Department of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale) 06120, Germany.
  • 3 Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
  • 4 Division of Bioanalytical Chemistry, Research Center Borstel, Leibniz Lung Center, Borstel 23845, Germany.
  • 5 Thematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Borstel 23845, Germany.
  • 6 Institute of Inorganic Chemistry, Karlsruhe Institute of Technology (KIT), Engesserstraße 15, Karlsruhe 76131, Germany.
  • 7 Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, 9000 Gent, Belgium.
  • 8 Department of Pharmaceutical Sciences, Division of Pharmacognosy, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
  • 9 German Center for Lung Research (DZL), Airway Research Center North (ARCN), Research Center Borstel, Leibniz Lung Center, Borstel 23845, Germany.
  • 10 Kiel Nano, Surface and Interface Sciences (KiNSIS), Kiel University, Kiel 24118, Germany.
PMID: 39698258 DOI: 10.1021/acsptsci.4c00558
Abstract

BTZ043 is an 8-nitro-1,3-benzothiazin-4-one with potency against multidrug-resistant Mycobacterium tuberculosis. Low solubility and hepatic metabolism are linked to poor oral bioavailability. Amorphous drug nanoparticles (ADN) were formulated to improve the bioavailability. Comparative pharmacokinetics of BTZ043 ADN following intranasal (2.5 mg kg-1) and oral administration (25 mg kg-1) in Balb/c mice was investigated using oral BTZ043 drug suspensions (neat; 25 mg kg-1) as a standard-of-care reference. Plasma exposure following oral ADN administration was 8-fold higher than for oral neat BTZ043. Intranasal ADN increased plasma exposure 18-fold compared to oral neat BTZ043 after dose normalization. BTZ043 was detectable in lung lining fluid following ADN administration, but not after oral neat BTZ043 dosing. BTZ043 was cleared faster from the lung and plasma following intranasal administration with a shorter time above the minimum inhibitory concentration (MIC) compared to oral ADN. Since time > MIC is reported to drive activity, oral ADN may represent a promising delivery strategy for BTZ043.

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