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Open Access Research article

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

Marc A von Mach*, Jürgen Burhenne and Ludwig S Weilemann

BMC Clinical Pharmacology 2006, 6:6  doi:10.1186/1472-6904-6-6

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Accumulation of sulphobutylether beta cyclodextrin sodium in patients under renal replacement therapy

Quanren He   (2007-03-07 15:00)  CyDex, Inc. 10513 W 84th Terr, Lenexa, KS 66214, USA email

To the Editor,

Recently, I enjoyed reading a paper in in BMC Clinical Pharmacology from von Mach et al. on blood levels of sulphobutylether-beta-cyclodextrin (SBE-beta-CD) in renally compromised patients treated with intravenous voriconazole (Vfend I.V) [1]. The authors observed an accumulation of SBE-beta-CD in the blood without any evidence of toxicity to the kidney in patients treated with Vfend I.V. It is a very interesting clincial study with Vfend I.V. The accumulation of SBE-beta-CD, the excipient for Vfend I.V under renal dysfunction, is predictable, as it is eliminated through urine by the kidney at the glomerular filtration rate (GFR) [2]. The safety of SBE-beta-CD in patients with renal insufficiency is a very interesting and important topic, as SBE-beta-CD can produce vacuoles in kidney observed in nonclinical studies. To help readers better understand the findings by von Mach et al., the following issues need to be discussed.

It is most important to emphasize that there was no evidence of toxicity, as was stated by the authors, regardless of the apparent increased levels of SBE-beta-CD in the blood. As the authors described, this lack of toxicity was expected based on comparison to blood levels associated with toxicity in animal models. The analysis of renal functions prior to and upon Vfend administration is very important, and these data could be presented in the article. The dosage regimen and how the effect of dialysis on SBE-beta-CD elimination was evaluated should be clearly described in the text so that readers understand how the patients were treated. The blood levels of drugs following Vfend infusion should be determined to assess the effects of dialysis on drug clearance prior to and after dialysis therapy. From Table 1, it is evident that evaluations were not conducted that way, leading to possible misinterpretation of dialysis effects. For example, patient #1 had SBE-beta-CD at a level of 98.3 microgram/ml before dialysis and 145 microgram/ml after dialysis the same day. This was inconsistent with the previous findings that hemodialysis resulted in a clearance of 55 ml/min in patients with renal insufficiency [2]. On the same day, it seems that patient #1 received four Vfend injections. When the blood was taken following Vfend infusion is not specified, though it is stated that the trough plasma levels of voriconazole and SBE-beta-CD were measured. It seems from Table 1 that the blood collection among the four subjects was conducted randomly, which reduced the comparability of blood drug levels among these subjects. The blood levels of SBE-beta-CD were presented, but data for a lack of nephrotoxic evidence as the authors stated were not presented. The clearance of SBE-beta-CD is equivalent to glomerular filtration rate (GFR) in normal subjects and is linearly correlated to creatinine clearance [2]. The decreased clearance of SBE-beta-CD could reflect reduced creatinine clearance. The total accumulated dose of SBE-beta-CD needs to be clearly defined, otherwise it was incorrect to simply multiply a value of Vd. Evidently the accumulated dose was not 100 mg/kg. The blood level of SBE-beta-CD was determined randomly, and blood SBE-beta-CD could have been cleared to some extent by dialysis and by the kidneys. Thus, the calculated value based on randomly analyzed blood level of SBE-beta-CD for accumulated dose was only correct for the specific time point. The minimal lethal dose for SBE-beta-CD has not been established, but it is clear that the minimal lethal dose is higher than 2000 mg/kg. Even at 3000 mg/kg in daily, repeated, i.v bolus injections for one month in the rat, no lethality was observed [2].

Liposomal amphotericin B is more toxic to kidney than Vfend [2]. It should not be an alternative to Vfend I.V for patients with renal impairment. The histopathological changes in kidney following SBE-beta-CD consist of vacuolation of tubular epithelial cells without any evidence of adverse functional damage, cell death, or degeneration. The characteristics of histopathological changes upon treatment with SBE-beta-CD are considerably different from those caused by aminoglycosides. The mechanisms of SBE-beta-CD renal changes have not been defined.

References

1. von Mach MA, Burhenne J, Weilemann LS. Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy. BMC Clin Pharmacol 2006; 6: 6.

2. FDA Antiviral Drugs Advisory Committee – Briefing Document for Voriconazole (Oral and Intravenous Formulations) [http://www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_01_Pfizer.pdf].

Competing interests

The author for the comments is currently holding a position of Senior Scientist in CyDex, Inc. as a toxicologist. CyDex, Inc. invests commercialization of SBE-beta-CD technology in areas of drug development. However, the author made the above comments solely based on his observation and judgement of science. The opinion presented in the comments does not represent the company or any other parts but his own

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