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

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 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.

Comparison between Colistin Sulfate Dry Powder and Solution for Pulmonary Delivery

“…The faster absorption was characterized by a Km value, i.e., the COLI concentration in the ELF for which the transfer rate from the ELF compartment to the central compartment is Vmax/2, which was significantly (six times) lower for INU-COLI particles than for COLI solutions (Appendix D Table A1). This result is in agreement with the work of Lin et al [10], who also found a higher COLI rate of absorption after pure COLI powder intratracheal delivery than after the delivery of COLI as a solution. In their study, Lin et al [10] observed a reduction in plasma Tmax measured after administration of the COLI dry powder (10 min-first sampling time) compared to that obtained after administration of the COLI solution (20 to 30 min).…”

“…This result is in agreement with the work of Lin et al [10], who also found a higher COLI rate of absorption after pure COLI powder intratracheal delivery than after the delivery of COLI as a solution. In their study, Lin et al [10] observed a reduction in plasma Tmax measured after administration of the COLI dry powder (10 min-first sampling time) compared to that obtained after administration of the COLI solution (20 to 30 min). In the present study, Tmax and plasma Cmax were equal to 0.5 h and 0.33 mg/L, respectively, whatever the formulation used, so the difference in systemic absorption rate had little impact on these parameters.…”

“…Thus non-significantly different typical bioavailabilities of 64% (RSE = 6%) were obtained after pulmonary administration of INU-COLI powder, INU-COLI solution, or COLI solution (Appendix D Table A1). This observation is in accordance with the results published by Lin et al [10], where they described similar systemic bioavailabilities (~46.5%, RSE = 8.43%) measured in rats after intratracheal delivery of pure COLI solution and pure COLI powder at a dose of 0.66 mg/kg. After pulmonary administration, COLI concentrations were much higher in ELF than in plasma, whatever the formulation used.…”

“…Colistin sulfate dry powder for inhalation has recently regained attention [7][8][9][10]. In a past study, the pulmonary function of patients and volunteers was evaluated after inhalation of pure COLI sulfate blended with lactose dry powder [11].…”

“…Consequently, the development of cationic COLI-based formulations for inhalation has recently regained attention [7][8][9][10]. For antibiotics, the aim of pulmonary inhalation is to administer large doses in a short time frame and in a reproducible manner.…”