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Accumulation of sulphobutylether-cyclodextrin in critically ill patients with acute renal insufficiency undergoing extended daily dialysis and treatment with intravenous voriconazole

Abstract number: R2137

Objectives: Cyclodextrin derivates are used as solvent vehicle for poorly water-soluble drugs such as voriconazole or itraconazole. They are mainly cleared by the kidney with the consequence of accumulation in patients with renal insufficiency. Therefore, use of intravenous administration forms of voriconazole and itraconazole are not recommended for this patient population. In addition, there are very limited pharmacokinetic (PK) data regarding of cyclodextrin accumulation in patients receiving any form of hemodialysis.

Methods: In this investigation 4 critically ill patients (3 women, age 60–79 years) with anuric acute renal failure were treated empirically with 4 mg per kg body weight intravenous voriconazole twice a day for invasive fungal infections. Extended daily dialysis (EDD) over a period of 8 h was performed daily using the GENIUS® batch dialysis system (Fresenius Medical Care, Germany) with a polysulphone high-flux dialyzer (F60S, surface area 1.3 m2; Fresenius Medical Care), a dialysate flow of 180 mL/min and a blood flow of 180 mL/min. On days 1 and 5 blood samples were collected before and at different time points up to 12 h after medication. sulphobutylether-b-cyclodextrin (SBECD) and voriconazole plasma concentrations were determined by a validated HPLC method.

Results: Tolerability of the treatment with intravenous voriconazole was good. No serious or dialysis related adverse events were observed. The SBECD plasma concentration–time curves of days 1 and 5 are shown in Figure 1. There was a clear accumulation of cyclodextrin on day 5 to see on higher peak and trough levels. The AUC0–12 (1598 vs. 4584 mg x h/L) and the terminal elimination half-life (8.7 vs. 15.1 h) were increased, too. Single and multiple dose PK parameters of voriconazole, however, were comparable with those from healthy control groups given in the literature.

Conclusions: Our data indicate an accumulation of SBECD in renal insufficient critically ill patients treated with intravenous voriconazole and EDD. Fortunately, no toxic effects were observed, although the accumulated dose was lower but comparable with those used in previous toxicity studies with animals. On the other hand EDD does not affect the pharmacokinetics of voriconazole.

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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