Pulmonary Pharmacokinetics of Colistin Following Administration of Dry Powder Aerosols in Rats [PublishAheadOfPrint]

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 (IV) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg) or IV 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 IV administration. The model-estimated clearance from the central plasma compartment was 0.271 L/h/kg (standard error [SE] = 2.51%). Transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (CL_ELF,Plasma= 4.03 x 10^-4 L/h/kg, SE = 15%). DPI appeared to have a faster rate of absorption (T_max,DPI ≤10 min) than nebulization (T_max,Neb 20-30 min), but similar systemic bioavailability (~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 similar PK and safety profiles. The PK and histopathological information obtained are critical for the development of optimal aerosolized colistin regimens against Gram-negative lung infections.

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