Re: Severe Interaction Between Methotrexate and a Macrolide-like Antibiotic In the Journal, Thyss et al. (J) re- ported that co-administration of high- dose methotrexate and the macro- lide-like antibiotic pristinamycin re- sulted in prolonged elimination of methotrexate and subsequent severe mucositis and neutropenia. Because there is structural similarity between the new immunosuppressive agent tacro- limus and macrolide antibiotics, a similar interaction is of potential con- cern when this agent is administered with methotrexate. In addition, Kortsanje (2) reported that the combina- tion of cyclosporine and methotrexate prolongs the elimination of both drugs and recommended that the combination be avoided. Despite the potential for drug interactions, low-dose methotrex- ate is used in the bone marrow transplant setting with cyclosporine to prevent graft-versus-host disease and is being investigated with tacrolimus (5- 5). We evaluated methotrexate con- centrations following low-dose therapy given with cyclosporine or tacrolimus in six allogeneic bone marrow transplant patients (four patients with CML and two with AML). All patients signed a written consent approved by the institu- tional review board and received the same supportive care therapies and con- ditioning regimen of busulfan, cyclo- phosphamide, and cytarabine. Three patients received cyclosporine (3 mg/kg per day) by continuous infusion, and three patients were administered tacro- limus (0.03 mg/kg per day), starting the day before bone marrow infusion. All patients received methotrexate (15 mg/m 2 ) on the first day following bone marrow transplantation (day +1). They received methotrexate (10 mg/m 2 ) on days +3, +6, and +11. Blood samples were obtained from the patients 24 hours after each methotrexate dose and analyzed for methotrexate concentration by fluorescent photometry immuno- assay (TDx; Abbott Laboratories, Chicago, IL) with a detection limit of 0.02 \\M. Folinic acid rescue (5 mg ad- ministered orally or intravenously every 6 hours x 4 doses) was initiated 24 hours after days +3, +6, and +11 of methotrexate administration. Of the 19 samples obtained, all con- centrations except one were below 0.05 |iM, with 50% of the concentrations being nonmeasurable (Table 1). In one patient who was administered cyclo- sporine, the concentration of metho- trexate on day +12 was 0.06, but it was below detection limits on day +13 fol- lowing administration of folinic acid. Toxic effects, including duration of neutropenia and mucositis, were similar between patients treated with cyclo- sporine and tacrolimus and to those toxic effects reported by Storb et al. (4). In our series, 95% of the metho- trexate concentrations obtained 24 hours following a dose remained below the range recommended for administration of folinic acid rescue (<0.05 \iM) (6). In another report, Nevil et al. (7) found that folinic acid rescue decreased hematologic, gastrointestinal, and he- patic toxic effects in bone marrow transplant patients receiving low-dose methotrexate with cyclosporine, even when methotrexate concentrations were less than 0.05 \iM. Given the low and often nonmeasurable concentrations achieved, it is difficult to make any cor- relation between methotrexate con- centrations and regimen-related toxicity. When low doses of methotrexate are used, the detection of drug interactions may also be confounded by the limited ability of assays to detect concentrations in the range of 0.01-0.05 \xM. In bone marrow transplant patients receiving low-dose methotrexate with cyclosporine or tacrolimus, we found methotrexate concentrations obtained 24 hours after a dose was administered did not significantly alter clinical care. We now routinely administer folinic acid rescue following administration of methotrexate and obtain concentrations only if patients have risk factors for prolonged elimination or toxicity of methotrexate, such as renal failure, as- cites, or pleural effusion. While it is possible that an interaction between methotrexate and cyclosporine or tacro- limus may occur, we believe that this in- teraction, if any, in bone marrow transplant patients is of no clinical sig- nificance. SUZANNE P. Dix Bone Marrow Transplantation STEVEN M. DEVINE ROBERT B. GELLER Leukemia Service JOHN R. WINGARD Bone Marrow Transplant Program Emory University Hospital Atlanta, GA References (/) Thyss A, Milano G, Renee N, Cassuto- Viguier E, Jambou P, Soler C. Severe interac- tion between methotrexate and a macro- lide-like antibiotic [letter]. J Natl Cancer Inst 1993:85:582-3. (2) Kortsanje MJ. Cyclosporine and metho- trexate: a dangerous combination. Am Acad Dermatol 1990:23:320-1. (3) Bearman SI, Appelbaum FR, Back A, Peter- sen FB, Buckner CD, Sullivan KM, et al. Regimen-related toxicity and early post- transplant survival in patients undergoing bone marrow transplantation. J Clin Oncol 1988:6:1562-8. (4) Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-35. (5) Nash RA, Etzioni R, Storb R, Furlong T, Gooley T, Anasetti C, et al. Tacrolimus (FK506) alone or in combination with Table 1. Methotrexate concentrations* Concentrations of methotrexate 24 h after dose, \iM Patient No. 1 2 3 4 5 6 Drug Tacrolimus Tacrolimus Tacrolimus Cyclosporine Cyclosporine Cyclosporine Day+2 <0.02 <0.02 — 0.04 <0.02 0.04 Day+4 <0.02 — <0.02 0.02 <0.02 <0.02 Day+7 <0.02 <0.02 — <0.02 0.02 <0.02 Day+ 12 0.03 <0.02 — 0.06 0.02 — *Comparison of methotrexate concentrations 24 hours after a dose in six bone marrow transplant patients receiving tacrolimus or cyclosporine in combination with low-dose methotrexate. Journal of the National Cancer Institute, Vol. 87, No. 21, November 1, 1995 CORRESPONDENCE 1641 Downloaded from https://academic.oup.com/jnci/article-abstract/87/21/1641/938797 by guest on 07 January 2019