Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

Abstract

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL_CR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL_CR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.

Keywords: dosing adjustment; drug exposure; polymyxins.

FIG 1

Correlation between observed and best-fit concentrations. (A) Standard two-stage approach. (B) MAP-Bayesian approach. The solid line depicts the line of best fit; the dashed line is the line of identity where y = x.

FIG 2

Comparison of overall drug exposures stratified by renal function. Data means ± the standard deviations. Note that the normalized AUC was adjusted to 1 mg/kg of polymyxin B daily.