Pharmacokinetics of sulfobutylether-beta-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemodiafiltration

Abstract

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 +/- 0.6 h (Genius dialysis) to 2.4 +/- 0.9 h (hemodialysis) and 2.0 +/- 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.

FIG. 1.

Measured SBECD concentrations in patients with end-stage renal failure on renal replacement therapy. The fastest decline in concentrations was observed during hemodiafiltration. Concentrations are shown as median (continuous line) and interquartile range (broken lines). VRC, voriconazole.

FIG. 2.

SBECD extracorporeal clearance in 14 patients with end-stage renal failure on different renal replacement therapies, Genius dialysis (GD), hemodialysis (HD), or hemodiafiltration (HDF), as determined based on dialysate measurements. The median values are shown as short black lines. Each symbol is the value for one patient.

FIG. 3.

Predicted SBECD concentrations after repeated administration of 6,600 mg SBECD in patients with normal renal function, impaired renal function, and renal failure without hemodialysis (A), renal failure with hemodialysis every 2 days (B), renal failure with hemodialysis every day (C), and hemodialysis every 12 h during VRC infusion (D). The parameter values were as follows: CL_tot = 8.5 liters/h and V = 23 liters for normal renal function; CL_tot = 1.8 liters/h and V = 24.8 liters for impaired renal function (based on data from Abel et al. [1]); and CL_tot,off = 0.8 liter/h, CL_tot,on = 5.5 liters/h, and V = 19 liters for renal failure (based on data from the present study). CL_crea, creatinine clearance; VRC, voriconazole.