This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sung, J. C.
Right arrow Articles by Edwards, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sung, J. C.
Right arrow Articles by Edwards, D. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2009, p. 1338-1343, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01389-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Dry Powder Nitroimidazopyran Antibiotic PA-824 Aerosol for Inhalation{triangledown}

Jean C. Sung,1 Lucila Garcia-Contreras,2 Jarod L. VerBerkmoes,1 Charles A. Peloquin,3 Katharina J. Elbert,1 Anthony J. Hickey,2* and David A. Edwards1*

Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138,1 University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, North Carolina 27599,2 National Jewish Medical and Research Center, Denver, Colorado 802063

Received 15 October 2008/ Returned for modification 10 November 2008/ Accepted 6 January 2009

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.

* Corresponding author. Mailing address for David A. Edwards: Harvard School of Engineering and Applied Sciences, 322 Pierce Hall, 29 Oxford Street, Cambridge, MA 02138. Phone (617) 495-1328. Fax: (617) 495-9837. E-mail: dedwards{at}seas.harvard.edu. Mailing address for Anthony J. Hickey: University of North Carolina at Chapel Hill, 1310 Kerr Hall, CB #7360, Chapel Hill, NC 27599. Phone (919) 962-0223. Fax: (919) 966-0197. E-mail: ahickey{at}unc.edu

{triangledown} Published ahead of print on 12 January 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1338-1343, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01389-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»