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Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e00973-17. doi: 10.1128/AAC.00973-17. Print 2017 Nov.

Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats.

Author information

1
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
2
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
3
Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
4
Department of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, North Carolina, USA.
5
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia kim.chan@sydney.edu.au jian.li@monash.edu.
6
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia kim.chan@sydney.edu.au jian.li@monash.edu.

Abstract

Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10-4 liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.

KEYWORDS:

colistin; disposition; dry powder; polymyxin; pulmonary delivery

PMID:
28807905
PMCID:
PMC5655076
DOI:
10.1128/AAC.00973-17
[Indexed for MEDLINE]
Free PMC Article

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