Interaction between voriconazole and tacrolimus in a kidney-transplanted patient

Michel Tintillier1, Lotti Kirch1, Eric Goffin2, Charles Cuvelier1 and Jean-Michel Pochet1

1 Department of Internal Medicine and Nephrology Clinique Sainte-Elisabeth Namur2 Department of Nephrology Cliniques Universitaires Saint-Luc Brussels Belgium Email: m.tintillier{at}ibelgique.com

Sir,

Infections are common life-threatening complications of long-term immunosuppressive therapy [1]. Among these, yeast infections are difficult to treat not only because of the context of immunosuppression, but also because of the pharmacokinetic properties of the antifungal agents, which inhibit the metabolism of calcineurin inhibitors, leading to an increase in the serum concentration and resulting in renal toxicity [2,3].

A 55-year-old male kidney transplant recipient was started on voriconazole for skin infection of the lower limbs due to Pseudallescheria boydii. End-stage renal failure secondary to medullary cystic kidney disease led to a cadaver renal transplantation 4 years earlier. His medical history also included severe bilateral peripheral vascular disease, ischaemic cardiomyopathy, arterial hypertension, chronic cholestasis of unknown aetiology (despite three hepatic biopsies) and hypercholesterolaemia. His treatment included tacrolimus 4 mg/day, prednisolone 7.5 mg/day, ciprofloxacin 1000 mg/day, cefadroxil 1000 mg/day, atenolol 2.5 mg od, furosemide 60 mg/day, lisinopril 20 mg/day, aspirin 160 mg/day, omeprazole 20 mg/day, pravastatin 20 mg/day, allopurinol 100 mg/day, dipyridamole 200 mg/day and molsidomine 16 mg/day.

Treatment with itraconazole was initiated 1 month before admission, concomitantly with a 50% reduction of the tacrolimus dosage (2 mg/day). Itraconazole was replaced by voriconazole after 1 month, because no clinical improvement had occurred. Upon start of oral voriconazole (4 mg/kg bid), tacrolimus trough level, previously stable and <12 ng/ml (aimed therapeutic interval: 5–12 ng/ml), increased markedly after 7 days (20 ng/dl after 10 days and 25 ng/dl after 17 days) and was associated with an impairment of renal graft function (serum creatinine rising from 1.2 to 1.9 and 3.9 mg/dl after 10 and 17 days, respectively). The tacrolimus dosage was reduced further and was completely withdrawn over 3 days, ending with a dosage of 0.5 mg every other day, and then a gradual recovery of the previous renal function was seen.

Voriconazole (V-Fend®; Pfizer) is a new second-generation triazole antifungal agent that demonstrates excellent activity against a wide variety of yeasts and moulds. It is generally well tolerated and is effective against Candida, Aspergillus and unusual organisms, such as Fusarium and P. boydii [2,4]. The mechanism of action of voriconazole, similar to that of all azole agents, is inhibition of the action of cytochrome P-450 (CYP-450)-dependent 14 x-lanosterol demethylation [2].

Because voriconazole is metabolized by the hepatic CYP-450 systems, drug interaction with calcineurin inhibitors occurs, resulting in increased serum concentration and sometimes leading to renal toxicity [3,5]. In this case, we present a case with a nephrotoxic effect of tacrolimus and voriconazole co-administration, despite a 50% reduction of tacrolimus. This severe interaction is clinically important and more pronounced than earlier described interactions with tacrolimus and other azole drugs. Perhaps, in this case, the interaction might have been aggravated by the chronic cholestasis our patient was suffering from.

Co-administration of calcineurin inhibitors with voriconazole is possible, though a reduction in the immunosuppressive drug dosage and a close monitoring of their trough levels have to be arranged [3,5]. Clinicians should be aware of this harmful drug interaction in order to avoid potential severe renal graft dysfunction, in particular in patients with chronic hepatopathy and cholestasis.

Conflict of interest statement. None declared.



   References
 Top
 References
 

  1. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751[Free Full Text]
  2. Sanati H, Belanger P, Fratti B, Ghannoum M. A new triazole, voriconazole (Uk-09, 496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother 1997; 41: 2492–2496[Abstract]
  3. Venkataramanan R, Zang S, Gayowski T, Singh N. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in liver microsomes. Antimicrob Agents Chemother 2002; 46: 3091–3093[Abstract/Free Full Text]
  4. David SM. Making best use of the newer antifungal drugs. Infect Med 2003; 20: 392–399[ISI]
  5. Pai M, Allen S. Voriconazole inhibition of tacrolimus metabolism. Clin Infect Dis 2003; 36: 1089–1091




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Tintillier, M.
Articles by Pochet, J.-M.
PubMed
PubMed Citation
Articles by Tintillier, M.
Articles by Pochet, J.-M.