Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis

Abstract

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

FIG 1

Plasma concentrations of CMS (left) and colistin (right) measured in ICU-HD patients. Times are relative to the last dose.

FIG 2

Normalized prediction distribution errors (NPDE) as a function of time from previous administration for CMS (left) and colistin (COLI) (right) plasma concentrations. Results are presented for each visit with a PK assessment (OCC, occasion).

FIG 3

Plasma concentration-time profiles of CMS (left) and colistin (right) after single-dose administration of CMS (3 MIU), predicted from PK parameter values corresponding to a typical ICU-HD patient (black full line), a typical ICU-85 patient (black dashed line), and a virtual ICU-00 patient (gray full line).

FIG 4

Simulations of colistin plasma concentration-time profiles in ICU-HD patients receiving a 4-hour HD session on day n and dosed with 1.5 MIU q12h of CMS. The CMS dose planned before the HD session was postponed to immediately after the session and was 3 MIU. Curves were simulated with different values of CMS and colistin HD clearances reported in the literature, i.e., 94.8, 90, and 94.8 ml/min for CMS and 56.7, 137, and 66.5 ml/min for colistin (solid grey line, solid black line, and dashed black line), respectively (5, 7, 8). PK parameter values—except HD clearances—were fixed to estimates of the present analysis.

FIG 5

Probability of target attainment (PTA) of colistin in ICU-HD patients dosed with 1.5 MIU q12h of CMS on days without HD for nonpulmonary (dashed line) and pulmonary (solid line) infections.