Inhaled Adjunct Therapy with Second-Line Drug Candidates for Dose Reduction in Chemotherapeutic Regimens for Multi-drug-Resistant Tuberculosis.
Mycobacterium tuberculosis
dry powder inhalation
multidrug resistance
sutezolid TBA-354
Journal
AAPS PharmSciTech
ISSN: 1530-9932
Titre abrégé: AAPS PharmSciTech
Pays: United States
ID NLM: 100960111
Informations de publication
Date de publication:
08 Jun 2023
08 Jun 2023
Historique:
received:
19
04
2023
accepted:
17
05
2023
medline:
12
6
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
epublish
Résumé
Chemotherapy of multi-drug-resistant tuberculosis (TB) requires prolonged administration of multiple drugs. We investigated whether pulmonary delivery of minute doses of drugs, along with reduced oral doses of the same agents, would affect preclinical efficacy. We prepared dry powder inhalation (DPI) formulations comprising sutezolid (SUT), the second-generation pretomanid analog TBA-354 (TBA), or a fluorinated derivative of TBA-354 (32,625) in a matrix of the biodegradable polymer poly(L-lactide). We established formulation characteristics, doses inhaled by healthy mice, and preclinical efficacy in a mouse model of TB. Oral doses of 100 mg/kg/day or DPI doses of 0.25-0.5 mg/kg/day of drugs SUT, TBA-354, or 32,625 administered over 28 days were sub-optimally effective in reducing lung and spleen burden of Mycobacterium tuberculosis (Mtb) in infected mice. The addition of 0.25-0.5 mg/kg/day of SUT, TBA-354, or 32,625 as DPI to oral doses of 50 mg/kg/day was non-inferior in clearing Mtb from the lungs of infected mice. We concluded that adjunct therapy with inhaled second-line agents has the potential to reduce the efficacious oral dose.
Identifiants
pubmed: 37291443
doi: 10.1208/s12249-023-02585-w
pii: 10.1208/s12249-023-02585-w
doi:
Substances chimiques
TBA-354
0
Antitubercular Agents
0
Pharmaceutical Preparations
0
Powders
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
130Informations de copyright
© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.
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