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LETTER TO THE EDITOR |
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Year : 2014 | Volume
: 7
| Issue : 1 | Page : 105-107 |
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Safety of intravenous voriconazole in renal failure
Abhijit S Nair
Consultant Anesthesiologist, Care Hospitals, Banjara Hills, Axon Anesthesia Associates, Hyderabad, India
Date of Web Publication | 10-Dec-2013 |
Correspondence Address: Abhijit S Nair Flat no. 306, b- block, Ganga Kaveri Apartments, Begumpet, Shamlal Buildings, Hyderabad - 500 016, Andhra Pradesh India
Source of Support: None, Conflict of Interest: None | Check |
DOI: 10.4103/0975-2870.122810
How to cite this article: Nair AS. Safety of intravenous voriconazole in renal failure. Med J DY Patil Univ 2014;7:105-7 |
Sir,
Voriconazole is a triazole antifungal agent which is available in oral and intravenous preparations. The oral preparation is a film coated tablet available as 50/200 mg of active drug. The injectable form is supplied as a sterile lyophilized powder in a single use vial containing 200 mg of active drug and 3200 mg of Sulfobutyl ether betacyclodextrin (SBECD). [1] SBECD is a large cyclic oligosaccharide that is used as a solvent to make voriconazole suitable for intravenous use. Pharmacologically, SBECD is an inert agent with a terminal t ½ of 1.8 h in humans with normal renal function. SBECD is composed of 1,4 linked glucopyranose molecules that form a truncated cone with a hydrophilic outer surface and a hydrophobic cavity. This structure forms an inclusion complex which carries a lipophilic voriconazole in its center. [2] In patients with normal renal functions, SBECD is well tolerated even in repeated doses. A total of 95% SBECD is excreted by kidneys at a clearance equal to that of creatinine. However, SBECD is toxic in patients with compromised renal functions but is rapidly eliminated by hemodialysis or CRRT. Hence, caution must be exercised when using IV voriconazole in patients with renal failure/dysfunction who are not on any form of renal replacement therapy. [3] There is no point in reducing the intravenous dose of voriconazole in compromised renal function as it will result in inadequate anti-fungal effect. As far as possible, one must try and use the oral preparation of voriconazole as it does not require any dose adjustment in renal failure and it is significantly cheaper than its intravenous counterpart. [1] However, in conditions where oral voriconazole may not be effective (gastroparesis, upper abdominal surgeries etc.), intravenous voriconazole is inevitable. Careful monitoring of renal function is mandatory if renal impairment is present. However, if any form of RRT is ongoing, intravenous voriconazole should be used in full dose. [4] The question that comes to one's mind is if these are the issues with SBECD, then why should one use it as a solvent for voriconazole? The answer is that by including SBECD in voriconazole, its physical and chemical properties are locked within the solvent which would otherwise have got unstable. By using SBECD as the solvent, voriconazole becomes better soluble, becomes resistant to the effects of oxidation and external heat. This stability is provided by SBECD because it has multiple hydroxyl groups and by the ability to form inclusion complexes. [5]
Review of SBECD as solvent for voriconazole in renal failure:
Von Mach et al., [6] studied and published their study on four renal failure patients on intermittent dialysis in whom IV voriconazole with SBECD was used. They measured SBECD levels and concluded that although the levels achieved were comparable to toxic levels seen in animals, no toxic effects were seen in humans. Alvarez- Lerma et al., [4] studied use of IV voriconazole in 69 patients of which 26 (37.7%) had impaired renal function (serum creatinine > 1.5 mg/dl). Out of these 26 patients, 10 had Sr Creat > 2.5 mg/dl. Treatment continued for 13 days in patients with normal renal function and for 12 days in patients with altered renal function. Renal damage was noticed in 13 (30.2%) patients with normal renal function and in 4 (15.4%) patients with impaired renal function. They also observed that renal failure due to voriconazole therapy was associated with significantly higher mortality rate. Abel et al., [7] studied pharmacokinetics, safety, and tolerance of voriconazole in patients with renal impairment by recruiting volunteers in two prospective, multicenter, open- label, and parallel group studies. First group had 24 patients divided into four subgroups of six each. Subgroups were divided as: no renal impairment, mild, moderate, and severe renal impairment. Patients received 200 mg of oral voriconazole. Second group had two subgroups of six in each subgroup: 1st subgroup had no renal impairment and 2nd subgroup had moderate renal impairment. In both subgroups, patients received 6 mg/kg of IV voriconazole on 1st day followed by 3 mg/kg for next 6 days. In both groups, plasma levels of voriconazole and serum creatinine were assessed until 36 h after the last dose. They concluded that renal impairment doesnot affect pharmacokinetics of voriconazole. There is a strong correlation between SBECD clearance and creatinine clearance and elevated SBECD doesnot necessarily correlate with increased creatinine levels. Hafner et al., [8] studied pharmacokinetics of SBECD and intravenous voriconazole in patients with ESRD during treatment with two different hemodialysis systems: Genius dialysis and standard hemodialysis or hemofiltration with a high flux polysulfone membrane. They found that SBECD was eliminated during 6 h of RRT by all three methods whereas elimination of voriconazole was quantitatively insignificant. Luke et al., [2] reviewed the basic pharmacology of SBECD in animals, healthy volunteers, and subjects with renal dysfunction. They concluded that although plasma SBECD accumulates in those with renal dysfunction, there are no harmful effects on renal function. But they suggested that serum creatinine should be monitored in patients getting regular doses of IV voriconazole with SBECD. Luke et al., [9] studied pharmacokinetics of SBECD on hemodialysis by recruiting seven male patients with ESRD and six subjects with normal functions. They concluded that hemodialysis can significantly decrease the levels of SBECD in patients with ESRD. Neofytos et al., [3] studied the use of voriconazole in 166 patients by dividing them into three groups. A total of 42 (25.3%) had a Creatinine Clearance (CrCl) <50 ml/min who received intravenous voriconazole, 77 (46.4%) had a CrCl > 50 ml/min who received IV voriconazole and 47 (28.3%) had a CrCl < 50 ml/min who received oral voriconazole. They concluded that the route of administration and baseline renal function did not predict worsening of renal function on days 3, 7 and end of treatment. The strongest predictors were concomitant use of other drugs like penicillins, fluoroquinolones, immunosuppressants, and underlying liver impairment.
Conclusion | | |
SBECD as a solvent for intravenous voriconazole can cause worsening of renal functions in patients who have renal dysfunction. Patients who are already on some form of renal replacement therapy do not pose any concern as SBECD is effectively eliminated by dialysis. Also intravenous voriconazole is significantly costlier than oral preparation. Hence, whenever possible, it is safe to use oral voriconazole if the patient is on enteral feeds as oral preparation is devoid of any nephrotoxic substance. Also no dose adjustment is required in a patient of renal failure while using oral voriconazole.
References | | |
1. | Nickie DG. Voriconazole: The newest triazole antifungal agent. Proc Bayl Univ Med Cent 2003;16:241-8. |
2. | Luke DR, Tomaszewski K, Damle B, Schlamm HT. Review of the basic and clinical pharmacology of Sulphbutyl-beta-Cyclodextrin (SBECD). J Pharm Sci 2010;98:3291-301. |
3. | Neofytos D, Lombardi LR, Shields RK, Ostrander D, Warren L, Nguyen MH, et al. Administration of voriconazole in patients with renal dysfunction. Clin Infect Dis 2012;54:913-21. [PUBMED] |
4. | Alvarez-Lerma F, Allepuz- Palau A, Garcia MP, Angeles Leon M, Navarro A, Sanchez- Ruiz H. Impact of intravenous administration of voriconazole in critically ill patients with impaired renal function. J Chemother 2008;20:93-100. |
5. | Del Valle, Eva M Martin, Cyclodextrins and their uses: A review. Process Biochem. May 2004;39:1033-46. |
6. | 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. [PUBMED] |
7. | Abel S, Allan R, Gandelman K, Tomaszewski K, Webb DJ, Wood ND. Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies. Clin Drug Investig 2008;28:409-20. [PUBMED] |
8. | Hafner V, Czock D, Burhenne J, Riedel KD, Bommer J, Mikus G, et al. Pharmacokinetics of sulfobutyl-beta-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemofiltration. Antimicrob Agents Chemother 2010;54:2596-602. [PUBMED] |
9. | Luke DR, Wood ND, Tomaszewski KE, Damle B. Pharmacokinetics of sulfobutyl-ether-ß- cyclodextrin (SBECD) in patients on hemodialysis. Nephrol Dial Transplant 2012;27:1207-12. [PUBMED] |
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