Pharmacokinetic interaction between methotrexate and piperacillin/tazobactam resulting in prolonged toxic concentrations of methotrexate

Abstract

Sir, Methotrexate is an antimetabolite commonly used to treat a number of malignancies including acute lymphoblastic leukaemia, high-grade lymphomas and germ cell tumours. In high doses methotrexate has been shown to result in significant myelosuppression, mucositis, hepatotoxicity and renal failure. Methotrexate is eliminated mainly unchanged in the urine by glomerular filtration and proximal tubular transport. We identified a 50-year-old female with newly diagnosed Burkitt’s lymphoma who was treated with alternating monthly cycles of IVAC (ifosfamide, etoposide and high-dose cytarabine) and CODOX-M (cyclophosphamide, doxorubicin, vincristine and high-dose methotrexate). Cerebral spinal fluid disease was treated with alternating weekly intrathecal administration of methotrexate or cytarabine. The patient’s course was complicated by a febrile neutropenic event on day +10 of her first cycle of chemotherapy and piperacillin/tazobactam was initiated as empirical therapy. Long-term therapy with piperacillin/tazobactam was necessary due to the formation of cavitary pneumonia secondary to Pseudomonas aeruginosa. A significant drug interaction was suspected during the patient’s first cycle of CODOX-M. The serum methotrexate concentration failed to decrease below 0.05 mmol/L and appeared to plateau around 0.2 mmol/L (Figure 1). Cytotoxic methotrexate concentrations were sustained for 8 days and were only abated (i.e. fell below 0.05 mmol/L) by the discontinuation of piperacillin/tazobactam. During the patient’s second cycle of CODOX-M, piperacillin/tazobactam was not administered and serum methotrexate levels declined appropriately. The patient’s serum creatinine concentrations (average and standard deviation of 0.46 – 0.07 mg/dL first cycle and 0.47 – 0.03 mg/dL second cycle) and concurrent medications, aside from piperacillin/tazobactam, did not differ between the two cycles of CODOX-M. Methotrexate total body clearance fell to only 3% of normal in the presence of piperacillin/tazobactam (Table 1). Following the patient’s next scheduled dose of intrathecal methotrexate, the peak serum methotrexate concentration was measured to be 0.44 mmol/L, well within the cytotoxic range. Fortunately, the patient was no longer receiving piperacillin/ tazobactam at that time, and serum methotrexate levels fell to below 0.05 mmol/L within 24 h. Many agents are known to prolong methotrexate elimination including probenecid, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs) and weak organic acids. Penicillin is known to abolish tubular secretion of methotrexate in monkeys and reduce human organic anion transporter (hOAT)-mediated methotrexate elimination in an in vitro mouse model. Piperacillin was shown to reduce renal methotrexate clearance in rabbits as early as 1986. Only a single clinical case report of a piperacillin–methotrexate interaction has ever been documented. The weak organic acid and penicillin derivative, tazobactam, is also eliminated by glomerular filtration and tubular secretion; however, no evidence is available regarding its potential ability to impair methotrexate elimination. 0.01 0.1 1 10 10