Population pharmacokinetics of colistin and its prodrug colistin methanesulfonate following intravenous and pulmonary dosing in sheep

Background. Colistin is administered as its inactive prodrug colistin methanesulfonate (CMS) and is increasingly used as last-line therapy against multidrug-resistant Gram-negative bacteria. While pulmonary dosing of CMS is utilised in lung infections to reduce the risk of nephrotoxicity and neurotoxicity, there is a dearth of pharmacokinetic (PK) information on colistin and CMS. Quantitatively characterising the PK of colistin and CMS in a clinically relevant model supports the optimisation of pulmonary dosage regimens.

Objectives. To characterise the population PK of colistin and CMS in plasma and broncho-alveolar lavage fluid (BALF) following intravenous and pulmonary administration of both compounds.

Methods. Data were available from a four-way crossover study in six merino sheep. Each sheep received an intravenous or nebulised dose equivalent to 2.5 mg/kg colistin as colistin sulphate or CMS in each study period. Concentrations of colistin (administered as colistin sulphate or formed from CMS) and CMS in plasma and BALF were quantified via HPLC. Population PK modelling of all concentration data was performed in S-ADAPT (version 1.57) via the SADAPT-TRAN for pre- and post-processor.

Results. A model with three disposition compartments each for colistin and CMS, and linear elimination of both colistin and CMS had good predictive performance for intravenous administration of colistin sulphate and CMS. Elimination clearance (between subject variability) was 1.08 L/h (25%) for colistin and 1.97 L/h (4%) for CMS. No CMS or colistin was detected in BALF following intravenous dosing of colistin sulphate or CMS. After CMS dosing, the rise of colistin concentrations was delayed and this was explained by a large fraction of colistin formation occurring in the shallow peripheral compartment. The first-order conversion rate constant from CMS to colistin was 0.0573 1/h (13%). A model including a BALF and a peripheral lung compartment for each colistin and CMS, and linear conversion of CMS to colistin in BALF adequately described the BALF concentrations following pulmonary dosing. No colistin was detected in plasma following pulmonary colistin sulphate or CMS. Only two sheep had one or more detectable CMS plasma concentrations following pulmonary CMS dosing.

Conclusions. The PK of colistin and CMS in plasma and BALF was adequately described by a model with linear conversion and elimination. Similarities in the disposition of colistin and CMS between sheep and humans suggest that sheep may be a clinically relevant PK model. The low colistin concentrations in plasma following pulmonary administration may be due to its extensive binding to lung tissues.