Disposition of colistin in critically-ill patients on sustained low-efficiency dialysis: A population pharmacokinetic study

Abstract

Objectives: Although colistin (administered as colistin methanesulphonate [CMS]) is used to treat infections in critically-ill patients undergoing sustained low-efficiency dialysis (SLED), there is a paucity of information on appropriate dosing regimens. This study aimed to characterize the population pharmacokinetics (popPK) of colistin during SLED and evaluate the likelihood of antibacterial benefit and colistin nephrotoxicity for different regimens. Methods: A prospective popPK study included 13 critically-ill patients (six females) treated with CMS and receiving SLED (6–8 hours). For each subject, the PK of formed colistin was studied on a non-SLED day and a SLED day (n = 8 studied during SLED day first). A single intravenous daily dose (150 mg colistin base activity) was administered on a non-SLED day. On a SLED day, patients received 150 mg colistin base activity 12-hourly. Serial blood, urine and dialysate samples were collected over 24 hours on both days. Colistin plasma concentrations were measured by high-performance liquid chromatography. PopPK modelling and Monte Carlo simulations were performed. Results: A linear one-compartment disposition model well-described the data. The population mean apparent colistin body clearance, excluding SLED clearance, was 1.69 L/h (20.6% inter-individual variability [IIV], 42.1% inter-occasion variability). The apparent colistin SLED clearance was 3.49 L/h (41.7% IIV), i.e. 67.4% of total colistin clearance on a SLED day. The apparent volume of distribution was 50.2 L (23.0% IIV). Discussion: Colistin clearance was substantially higher during SLED; therefore, SLED should be accounted for in CMS dosing regimens. This project generated clinically applicable regimens, such as loading doses, to achieve required probabilities of target attainment in patients undergoing SLED.