title: Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder.
abstract: A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration-time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-∞ compared with IP delivery. The plasma AUC0-∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW 2037, Australia; JHL Biotech, Inc., Zhubei City, Hsinchu County 302, Taiwan, ROC.
authors.forename: John G Y
authors.initials: JG
authors.lastname: Chan
authors.affiliation: Centenary Institute, Sydney, NSW 2050, Australia; Discipline of Medicine, Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Anneliese S
authors.initials: AS
authors.lastname: Tyne
authors.affiliation: Centenary Institute, Sydney, NSW 2050, Australia.
authors.forename: Angel
authors.initials: A
authors.lastname: Pang
authors.affiliation: The Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia; Centre for Education and Research on Ageing, Concord Hospital, Concord, NSW 2139, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, NJ, USA; Faculty of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Perera
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Joseph C Y
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Centenary Institute, Sydney, NSW 2050, Australia; Discipline of Medicine, Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: The Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Hak Kim
authors.initials: HK
authors.lastname: Chan
authors.affiliation: The Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Duke
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW 2037, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW 2037, Australia. Electronic address: daniela.traini@sydney.edu.au.
authors.forename: Daniela
authors.initials: D
authors.lastname: Traini
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D008168:Lung / Q000737:chemistry; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D015233:Models, Statistical; D010949:Plasma / Q000737:chemistry; D011208:Powders / Q000008:administration & dosage; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000336:Aerosols; D000904:Antibiotics, Antitubercular; D011208:Powders; D012293:Rifampin; C018421:rifapentine
keywords: Aerosol delivery; Granuloma; Inhaled dry powder; Rifapentine; Tuberculosis