Pulmonary Pharmacokinetics of colistin following administration of dry powder aerosols in rats

Yu Wei Lin, Qi Tony Zhou, Yang Hu, Nikolas J. Onufrak, Siping Sun, Jiping Wang, Alan Forrest, Hak Kim Chan, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

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 intra-tracheally (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 4.03 104 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.

Original languageEnglish
Article numbere00973
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Colistin
  • Disposition
  • Dry powder
  • Polymyxin
  • Pulmonary delivery

Cite this

Lin, Yu Wei ; Zhou, Qi Tony ; Hu, Yang ; Onufrak, Nikolas J. ; Sun, Siping ; Wang, Jiping ; Forrest, Alan ; Chan, Hak Kim ; Li, Jian. / Pulmonary Pharmacokinetics of colistin following administration of dry powder aerosols in rats. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 11.
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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 intra-tracheally (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 4.03 104 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.",
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Pulmonary Pharmacokinetics of colistin following administration of dry powder aerosols in rats. / Lin, Yu Wei; Zhou, Qi Tony; Hu, Yang; Onufrak, Nikolas J.; Sun, Siping; Wang, Jiping; Forrest, Alan; Chan, Hak Kim; Li, Jian.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 11, e00973, 01.11.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zhou, Qi Tony

AU - Hu, Yang

AU - Onufrak, Nikolas J.

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AB - 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 intra-tracheally (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 4.03 104 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.

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