Extracorporeal clearance of colistin methanesulphonate and formed colistin in end-stage renal disease patients receiving intermittent haemodialysis: implications for dosing

Abstract

Objectives: Colistin, administered intravenously as its inactive prodrug colistin methanesulphonate (CMS), is being increasingly used. However, there is very limited information available on the impact of haemodialysis (HD) on the pharmacokinetics of CMS and formed colistin.

Patients and methods: A single 30 min intravenous dose of CMS (150 mg of colistin base activity) was administered to 10 patients undergoing HD. HD was performed from 1.5 to 5.5 h after the start of the CMS infusion. Serial blood samples were collected over 50 h, additional blood samples pre- and post-dialysis membrane at three timepoints during HD, dialysate samples at four timepoints during HD, and a cumulative urine sample over 24 h. CMS and colistin were determined by HPLC. Population modelling and determination of HD clearance by multiple methods was conducted.

Results: The average amount of CMS recovered in the dialysate was 30.6% of the dose administered. The concentrations of CMS and colistin in the plasma and the amounts of CMS recovered in the dialysate were well described by the population disposition model. The clearance of CMS by dialysis as estimated by population analysis based on systemic plasma concentrations and amounts in the dialysate was 4.26 L/h (26% coefficient of variation). The dialysis clearance determined from the pre- and post-membrane plasma concentrations was 5.67 L/h (21%) for CMS and 3.99 L/h (44%) for colistin. Thus, CMS clearance by dialysis from trans-cartridge extraction was ∼30% higher than when calculated based on the amount in dialysate, suggesting adsorption to the membrane.

Conclusions: Due to the extensive removal of CMS by dialysis, HD should be conducted at the end of a dosing interval and a supplemental dose should be administered.

Keywords: determination of extracorporeal clearance by multiple methods; polymyxins; population pharmacokinetics; renal replacement therapy.