title: Dry powder nitroimidazopyran antibiotic PA-824 aerosol for inhalation.
abstract: We formulated PA-824, a nitroimidazopyran with promise for the treatment of tuberculosis, for efficient aerosol delivery to the lungs in a dry powder porous particle form. The objectives of this study were to prepare and characterize a particulate form of PA-824, assess the stability of this aerosol formulation under different environmental conditions, and determine the pharmacokinetic parameters for the powder after pulmonary administration. The drug was spray dried into porous particles containing a high drug load and possessing desirable aerosol properties for efficient deposition in the lungs. The physical, aerodynamic, and chemical properties of the dry powder were stable at room temperature for 6 months and under refrigerated conditions for at least 1 year. Pharmacokinetic parameters were determined in guinea pigs after the pulmonary administration of the PA-824 powder formulation at three doses (20, 40, and 60 mg/kg of body weight) and compared to those after the intravenous (20 mg/kg) and oral (40 mg/kg) delivery of the drug. Oral and inhaled delivery of PA-824 achieved equivalent systemic delivery at the same body dose within the first 12 h of dosing. However, animals dosed by the pulmonary route showed drug loads that remained locally in the lungs for 32 h postexposure, whereas those given the drug orally cleared the drug more rapidly. Therefore, we expect from these pharmacokinetic data that pulmonary delivery may achieve the same efficacy as oral delivery at the same body dose, with a potential improvement in efficacy related to pulmonary infection. This may translate into the ability to deliver lower body doses of this drug for the treatment of tuberculosis by aerosol.
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 021381, USA.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Sung
authors.forename: Lucila
authors.initials: L
authors.lastname: Garcia-Contreras
authors.forename: Jarod L
authors.initials: JL
authors.lastname: Verberkmoes
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Elbert
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
authors.forename: David A
authors.initials: DA
authors.lastname: Edwards
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D006168:Guinea Pigs; D008297:Male; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011208:Powders
chemical_list: D000336:Aerosols; D000995:Antitubercular Agents; D009593:Nitroimidazoles; D011208:Powders; C410767:pretomanid