Substantial targeting advantage achieved by pulmonary administration of colistin methanesulfonate: Insights from a large animal model [PublishAheadOfPrint]

Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large animal model with similar pulmonary architecture to humans.

Six merino sheep (34-43kg) received an intravenous or pulmonary dose of 4-8 mg/kg CMS (sodium) or 2-3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) by HPLC. ELF concentrations were calculated via the urea method. CMS and colistin were co-modelled in S-ADAPT.

Following intravenous CMS or colistin, no concentrations were quantifiable in BALF. Elimination clearance was 1.97 L/h (4% inter-individual variability) for CMS (other than conversion to colistin) and 1.08 L/h (25%) for colistin. On average 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average (SD) ELF concentrations of formed colistin were 400 (243), 384 (187) and 184 (190) mg/L at 1, 4 and 24 h after pulmonary CMS. The population pharmacokinetic model well described CMS and colistin in plasma and ELF following intravenous and pulmonary administration.

Pulmonary dosing provided high ELF and low plasma colistin concentrations, i.e. a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate sheep are an advantageous model for translational research.

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