Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy

Mach, M.-A. von; Burhenne, Jürgen; Weilemann, L. S.

doi:10.1186/1472-6904-6-6

Cited by 88 publications

(41 citation statements)

References 11 publications

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“…This may be explained by differences in membrane material and surface area of the applied dialyzer as well as by differences in blood, dialysate, and ultrafiltrate flow rates. The extensive clearance observed in our study appears to be contradictory to the recent study of von Mach and coworkers (19) who observed a considerable increase of SBECD in four critically ill patients despite intermittent dialysis. In three of these patients, plasma SBECD concentrations of up to 580 mg/liter were observed.…”

Section: Discussioncontrasting

confidence: 56%

“…In three of these patients, plasma SBECD concentrations of up to 580 mg/liter were observed. In one of these patients, in whom concentrations were measured before and after dialysis on the same day, the SBECD concentration was only 3% lower after hemodialysis (19), indicating negligible elimination. The apparent discrepancy between this data and our data is likely due to the use of low-flux filter membranes (cutoff approximately 1,000 Da) by von Mach and high-flux filter membranes (cutoff approximately 20,000 Da) in our study.…”

Section: Discussionmentioning

confidence: 99%

“…SBECD is renally excreted (95% of the compound), and its clearance is linearly correlated with creatinine clearance. An increased SBECD exposure has been observed in patients with moderate renal impairment and renal failure (1,19). Preliminary data from four patients with end-stage renal failure on intermittent hemodialysis indicated an extracorporeal SBECD clearance of 3.3 liters/h and removal of approximately 46% of SBECD during 4 h of hemodialysis (12).…”

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confidence: 99%

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Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

Hafner

Czock

Burhenne

et al. 2010

Antimicrob Agents Chemother

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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.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

Hafner

Czock

Burhenne

et al. 2010

Antimicrob Agents Chemother

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“…Information on patients with impaired renal function is scarce. Three small studies on critically ill patients requiring hemodialysis showed accumulation of SBECD over time without observation of any toxic effects (3,4,10).…”

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confidence: 99%

Safety and Tolerability of Voriconazole in Patients with Baseline Renal Insufficiency and Candidemia

Lashof

Sobel

Ruhnke

et al. 2012

Antimicrob Agents Chemother

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h Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole. A cutely ill patients with candidemia often have comorbidities, such as renal failure, hepatic insufficiency, or respiratory failure. In a large randomized trial, voriconazole was shown not to be inferior to a regimen of amphotericin B deoxycholate followed by fluconazole for first-line treatment of candidemia in nonneutropenic patients and was associated with fewer adverse events (AE) than the comparator regimen (6). Based on these data, voriconazole has been approved for treatment of candidemia in nonneutropenic patients, but use of the intravenous (i.v.) formulation with sulfobutylether beta-cyclodextrin (SBECD) is not recommended in patients with renal insufficiency. Information on patients with impaired renal function is scarce. Three small studies on critically ill patients requiring hemodialysis showed accumulation of SBECD over time without observation of any toxic effects (3, 4, 10).We reviewed the use of i.v. voriconazole formulated with SBECD followed by oral voriconazole in a subset of candidemic patients with moderate or severe renal insufficiency from a recent comparative study and compared the treatment outcome and safety to those of patients who received the standard tre...

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“…However, caution should be exercised when IV voriconazole is used in patients with a creatinine clearance (CrCl) 550 mL/min or with IV itraconazole in patients with CrCl 530 mL/ min 7 . This is because the cyclodextrin component of these parenteral formulations can accumulate in patients with renal disease, and some animal studies suggest very high cyclodextrin may be associated with renal toxicity 58 . Voriconazole dose reduction is recommendations for patients with mild-to-moderate hepatic dysfunction 59 .…”

Section: Pharmacokinetics (Pk) and Therapeutic Drug Monitoring (Tdm)mentioning

confidence: 99%

Optimizing antifungal choice and administration

Andes¹

2013

Current Medical Research and Opinion

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Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy

Cited by 88 publications

References 11 publications

Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

Safety and Tolerability of Voriconazole in Patients with Baseline Renal Insufficiency and Candidemia

Optimizing antifungal choice and administration

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