1 Second Department of Internal Medicine, 2 Division of Artificial Kidney, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano-Ken 390-8621, Japan.
Sir,
Tacrolimus is used in renal and other organ transplantations for induction or rescue therapy. Tacrolimus therapy occasionally produces side-effects such as nephrotoxicity, cardiotoxicity, neurotoxicity, and glucose intolerance. Renal dysfunction is especially influenced by high blood tacrolimus concentration. Therefore it is important to control blood tacrolimus concentration within an adequate range.
Immunosuppressive agents sometimes result in infections that require antifungal agents. Many of these agents are known to interact pharmacologically with tacrolimus. Itraconazole is one of the azole antifungal agents. We observed an increase in blood tacrolimus concentration that resulted in tacrolimus nephrotoxicity during accompanying epidemic itraconazole therapy in an ABO-incompatible renal transplant patient.
Case.
We report on a 30-year-old, 56 kg male patient with a history of focal segmental glomerulosclerosis who received an ABO-incompatible renal transplantation from his father at Shinshu University Hospital in June 1998. Ten days before transplantation, itraconazole administration for prophylaxis was started orally at a dose of 100 mg/day. Oral tacrolimus administration was started 4 days before the operation at an initial dose of 0.15 mg/kg. Blood tacrolimus concentration was measured using the microparticle immunoassay method (MEIA). However, this concentration was 47.5 ng/ml on the day of the operation, and we stopped itraconazole administration, considering the interaction between tacrolimus and itraconazole. His post-transplant medications were started with prednisolone (60 mg/day), azathioprine (100 mg/day), deoxysupergualin (250 mg/day), anti-lymphocyte globulin (ALG, 1000 mg/day), and tacrolimus in varying doses. On the day of the operation, the tacrolimus dose was given as a continuous i.v. infusion at 0.05 mg/kg/day and was then adjusted to attain a blood concentration ranging from 20 to 40 ng/ml. From post-transplant day 8, oral tacrolimus (0.14 mg/day) and itraconazole (100 mg/day) were administered in two doses daily. For 3 days before the restart of itraconazole administration, the patient's blood tacrolimus concentration remained stable (ranging from 23 to 32 ng/ml). Serum itraconazole trough concentration was measured using high-performance liquid chromatography (HPLC).
The oral dose of itraconazole was increased to 200 mg/day on post-transplant day 17 to provide a concentration of between 200 and 400 ng/ml. Serum creatinine became 1.1 mg/dl on post-transplant day 5.
After the addition of itraconazole, the blood tacrolimus level increased to more than twice the previous level, with the gradual increase of creatinine level reaching 1.7 mg/dl on post-transplant day 14. On that day, the first graft biopsy was performed and histological findings revealed tubular vacuoles (compatible with tacrolimus-associated tubulopathy) but not acute rejection. As a result, the daily dose of tacrolimus was reduced to 0.11 mg/kg/day and adjusted to attain a blood concentration ranging from 20 to 25 ng/ml. However, blood tacrolimus level did not decrease to below 25 ng/ml until post-transplant day 33. Because the increase serum creatinine level had reached 2.2 mg/dl on post-transplant day 35, rebiopsy of the graft was performed.
Histological findings revealed tacrolimus-associated tubulopathy but no acute rejection. The daily oral dose of tacrolimus was decreased to 0.035 mg/kg/day. On post-transplant day 55, the level of serum creatinine became 1.8 mg/dl, so the patient was discharged. However, he was readmitted to our hospital on post-transplant day 87 with a serum creatinine level of 2.5 mg/dl. The results of urinalysis and urine chemistry suggested tacrolimus-associated tubulopathy; therefore, we changed tacrolimus to oral cyclosporin (CsA) at a dose of 3 mg/kg/day and ceased itraconazole administration on post-transplant day 100. The blood CsA concentration (a specific monoclonal fluorescence polarization immunoassay method; FPIA) was adjusted to attain a trough blood concentration ranging from 100 to 120 ng/ml with success. The level of serum creatinine gradually decreased to 1.9 mg/dl on post-transplant day 100 but did not fall below that level.
Discussion.
It has been reported that azole antifungal agents such as ketoconazole and fluconazole increase blood concentrations of CsA in organ transplant recipients [14]. Interactions between antifungal agents and tacrolimus have also been reported [57]. However, there are few reports about the interaction between itraconazole and tacrolimus with the measurement of these two drugs' blood concentrations in renal transplantation [8]. Our patient received itraconazole, which was associated with a rise in blood tacrolimus concentrations. The daily dose of tacrolimus was much less than that normally used when we adjusted the trough level to 20 ng/ml. This led us to believe that there was a pharmacokinetic drugdrug interaction between itraconazole and tacrolimus.
Tacrolimus is known to interact pharmacokinetically with many other drugs. The interactions between these drugs are thought to be caused by the inhibition of the cytochrome P-450 system. For example, INH induces the P-450 system and simvastatin inhibits the P-450 system. Clinically, interaction with the former drug induces rejection caused by enhanced metabolism of tacrolimus and with the latter drug produces nephrotoxicity by a reduced elimination of tacrolimus. We speculated that itraconazole interacted with tacrolimus through the P-450 system.
We measured the concentrations of serum itraconazole and its active metabolite (OH-itraconazole) using an HPLC method. Oral itraconazole readministration was started on post-transplant day 8. Itraconazole and OH-itraconazole concentrations increased in parallel. Trough concentration : - dose ratios (CDR) of tacrolimus are shown in Figure 1. Ten days after the addition of oral itraconazole readministration, CDR increased to more than twice the baseline value of post-transplant day 8 with the serum itraconazole concentration of the effective range. The ratio of the maximum CDR (post-transplant day 44) to baseline CDR (post-transplant day 8) is approximately 5.08.
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It is important to keep in mind that the tacrolimus therapeutic range is very narrow, so blood concentrations of tacrolimus should be monitored frequently, especially while azole antifungal agents are co-administered.
References