Reply to letter to the Editor to ‘Comment about the safety of intravenous voriconazole formulated with sulfobutylether beta-cyclodextrin’

Dear Editor,

First, we would like to thank the authors for their interest in our manuscript express our appreciation for their comment regarding the safety of intravenous voriconazole in patients with renal impairment or renal dysfunction. As stated in the summary of product characteristics of intravenous voriconazole [1,2], accumulation of the intravenous vehicle, sulphobutylether-beta-cyclodextrin (SBECD), occurs in patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min). This accumulation is due to the elimination of SBECD by glomerular filtration and reflected by a four-fold increase in the mean systemic exposure (AUC) of SBECD in subjects with moderately impaired renal function relative to normal controls. Based on the observation of nephrotoxicity of early, structurally different cyclodextrins and the consistent observation of exposure-dependent (reversible) vacuolation in kidney tissue of variable significance following administration of cyclodextrins including SBECD, in preclinical studies [3,4], the regulatory authorities in the U.S. and Europe recommend avoiding the use of intravenous voriconazole in patients with moderate and severe renal dysfunction [1,2].

In their comment, the authors reference several clinical studies that included patients with moderate to severe renal impairment who underwent treatment with intravenous voriconazole without deterioration of renal function or increase in morbidity or mortality rates. We concur with the authors’ assessment that the compound may be safely administered to individual patients with compromised renal function in situations where there is no alternative option. However, in general, severely ill patients treated in the intensive care unit, those following solid organ or hematopoietic cell transplantation and those with hematological malignancies considered for treatment with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in worsening renal function while on treatment. For example, in a large randomized clinical trial published by Walsh et al. who evaluated 837 patients randomized to receive voriconazole or liposomal amphotericin B (LAMB) at 3 mg/kg and day, 10.4% of those who received voriconazole had an >1.5 fold increase in serum creatinine levels; 7% of the patients who received voriconazole had an >2.0 fold increase in creatinine values which was not significantly different to those randomized to LAMB (7.6%), a compound with documented nephrotoxic potential; of note, nephrotoxicity in this trial correlated with coadministration of other nephrotoxic drugs [5].

We agree with authors’ that in the majority of the referenced studies assessing the nephrotoxicity of intravenous voriconazole in adult patients, there was no signal for a clinically relevant deterioration of renal function. Regarding pediatric patients and in particular the group of children aged <2 year, few data exist about the use of intravenous voriconazole and its impact on renal function.

We would like to conclude that although intravenous voriconazole appears to be safe in patients with moderate to severe renal impairment, an increased level of awareness is required as most patients have relevant comorbidities and comedications that may lead to worsening renal function, and a careful risk-benefit assessment is required for the justification of the off-label use of intravenous voriconazole in this situation.

Declaration of interest

A Tragiannidis has received grants from Merck Sharp & Dohme, Gilead, GSK, Sanofi; is a consultant to Pfizer and served at the speakers’ bureau of Gilead and MSD. AH Groll has received grants from Gilead, MSD, Pfizer and Schering-Plough; is a consultant to Astellas, Basilea, Gilead, MSD and Schering-Plough, and served at the speakers´ bureau of Astellas, Basilea, Gilead, MSD, Pfizer, Schering-Plough and Zeneus/Cephalon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.