title: Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation.
abstract: Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales 2006, Australia.|School of Pharmaceutical Sciences, Universiti Sains Malaysia , Pulau Pinang 11800, Malaysia.
authors.forename: Thaigarajan
authors.identifier: 0000-0002-1432-3092
authors.initials: T
authors.lastname: Parumasivam
authors.affiliation: Tuberculosis Research Program, Centenary Institute , Sydney, New South Wales 2042, Australia.|Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Anneliese S
authors.initials: AS
authors.lastname: Ashhurst
authors.affiliation: Tuberculosis Research Program, Centenary Institute , Sydney, New South Wales 2042, Australia.|Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Nagalingam
authors.affiliation: Tuberculosis Research Program, Centenary Institute , Sydney, New South Wales 2042, Australia.|Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006207:Half-Life; D008168:Lung / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced*; D011208:Powders / Q000008:administration & dosage / Q000009:adverse effects; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000904:Antibiotics, Antitubercular; D011208:Powders; D012293:Rifampin; C018421:rifapentine
keywords: aerosol delivery; inhalable rifapentine; pulmonary inflammation; toxicity; tuberculosis