Overcoming the effect of rifampin on the tacrolimus metabolism by itraconazole administration in an allogeneic hematopoietic stem cell transplant recipient

Abstract

Rifampin, one of the first-line agents for tuberculosis, has a great potential to induce the activity of the cytochrome P450 (CYP) enzyme, CYP 3A4, and lowers the concentration of calcineurin inhibitors such as tacrolimus and cyclosporine A (CsA). When calcineurin inhibitors and rifampin are coadministered, increasing the dose of calcineurin inhibitors is essential in maintaining therapeutic blood levels, but this often fails and results in the induction of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) or graft rejection after solid organ transplantation [1–6]. Another option is the administration of agents which could compete with the activity of rifampin upon CYP 3A4. We here present a case in which rifampin was coadministered with tacrolimus after allogeneic HSCT, and administration of oral-solution itraconazole successfully offset the effect of rifampin on the tacrolimus metabolism, resulting in the achievement of a therapeutic blood level of tacrolimus. A 50-year-old woman with myelodysplastic syndrome underwent bone marrow transplantation from an unrelated donor. Tacrolimus and short-term methotrexate were given for the prophylaxis of GVHD. Tacrolimus was given at an initial dose of 0.03 mg/kg by continuous intravenous infusion from day -1, and its dose was adjusted to maintain its blood level at 15–20 ng/ml during the first 4 weeks, followed by oral administration to maintain the blood level at 5–10 ng/ml. She developed acute GVHD of the skin on day 33 post-transplant, which was successfully treated with prednisolone. Prednisolone was given at a dose of 1 mg/kg for 7 days, then tapered, and discontinued on day 96 posttransplant. During prednisolone therapy, voriconazole at dose of 400 mg/day was orally given for the prophylaxis of fungal infection. Antifungal agents were not given thereafter. Around day 150 post-transplant, when tacrolimus was still being orally administered (3 mg/day) and its whole-blood trough level was around 5.5 ng/mL, pulmonary tuberculosis was diagnosed. Anti-tuberculosis chemotherapy consisting of rifampin (300 mg/day), isoniazid (300 mg/day), ethambutol (750 mg/day), and pyrazinamide (1200 mg/day) was initiated. Shortly after initiating this combination therapy, the trough level of tacrolimus became undetectable by automated microparticle enzyme immunoassay (minimum detectable level: 3.0 ng/ mL). Doubling the dose of tacrolimus to 6 mg/day failed to achieve a detectable level of tacrolimus. Oral-solution itraconazole was then initiated at a dose of 200 mg/day for the prophylaxis of fungal infection. The trough level of tacrolimus began to rise, and reached 5.7 ng/ml with 3 mg/ day of oral tacrolimus in 8 days after initiating itraconazole. The patient did not develop GVHD during or after the period of undetectable blood levels of tacrolimus, and fungal infection throughout the clinical course. The combination antituberculosis therapy was effective, and the pulmonary tuberculosis was cured after the 12-month therapy. Coadministration of oral-solution intraconazole with tacrolimus, rifampin, and three other anti-tuberculosis agents caused no clinically significant adverse events. As seen in the present case, rifampin has a great impact on the pharmacokinetics of calcineurin inhibitors, and markedly increases the dose requirement of calcineurin inhibitors to maintain a therapeutic blood level during rifampin therapy [1]. Increasing the dose of calcineurin inhibitors is not always effective, and the reduced levels T. Mori (&) Y. Aisa J. Kato Y. Nakamura T. Shimizu S. Okamoto Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: tmori@sc.itc.keio.ac.jp