Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences?

Abstract

The aim of this retrospective cohort study was to investigate the incidence of delayed methotrexate elimination in patients treated with high-dose methotrexate (≥1 g/m ) for haematological malignancy and to identify the impact of interacting drugs, especially proton-pump inhibitors (PPIs) and ranitidine. All patients treated with high-dose methotrexate over a 6 year period in the haematology department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) were included. Potential risk factors for delayed methotrexate elimination were tested in a generalized linear model by univariate analysis: patient age, gender, methotrexate dose, administration of PPI or ranitidine, and concomitant nephrotoxic drugs. A total of 412 cycles of methotrexate were administered to 179 patients. Proton-pump inhibitors were co-administered with methotrexate in 127 cycles and ranitidine in 192 cycles. Ninety-three cycles included no antacid drugs. A total of 918 plasma methotrexate assays were performed. Methotrexate concentrations were checked at 24 hours in 92% of cycles. Delayed methotrexate elimination was observed in 20.9% of cycles. A total of 63 cycles with delayed methotrexate elimination were only identified on plasma methotrexate measures at 72 hours: ie, plasma methotrexate was in the normal range at 24 and 48 hour post injection. Use of PPI/ranitidine or no antacid drugs did not increase risk of delayed elimination, with respectively delayed methotrexate elimination in 20.5%, 21.9%, and 19.4% of cycles (P = .89). Impaired baseline creatinine clearance showed significant association in univariate analysis. Fifteen patients showed grade 1 acute kidney injury, 1 grade 2, 2 grade 3, and none grade 4. For half of these cases, delayed methotrexate elimination was observed and the 2 grade 3 events appeared in patients treated with PPIs. This retrospective study suggests that there is no association between concomitant use of proton-pump inhibitors (pantoprazole and esomeprazole) or ranitidine and delayed methotrexate elimination.

Low Serum Albumin Level Is a Risk Factor for Delayed Methotrexate Elimination in High-Dose Methotrexate Treatment

“…The incidence rate of delayed MTX elimination in patients who received the HD-MTX regimen in our study was 23% (17 of 74 cycles), similar to previous reports. 10,11,21 The risk factors for delayed MTX elimination were osteosarcoma and low ALB level.…”

“…8 Despite these approaches, delayed elimination of MTX from the plasma, which can cause severe adverse effects such as acute renal failure, gastrointestinal toxicities, and myelosuppression, has been observed in some cases. 3,4,9,10 Therefore, risk factors for delayed MTX elimination need to be further clarified.Because MTX is excreted through the kidney, its clearance depends on renal function. 11 In addition to reduced renal functions, the delayed elimination of MTX from the plasma is associated with some drug interactions.…”

“…8 Despite these approaches, delayed elimination of MTX from the plasma, which can cause severe adverse effects such as acute renal failure, gastrointestinal toxicities, and myelosuppression, has been observed in some cases. 3,4,9,10 Therefore, risk factors for delayed MTX elimination need to be further clarified.…”

Diabetes is a risk factor for high-dose methotrexate-associated AKI in lymphoma patients

“…With high effectiveness brought by HDMTX than low dose of MTX, significant toxicities including nephrotoxicity, hepatotoxicity, mucositis, bone marrow suppression, and neurotoxicity follow at the same time [6]. MTX is cleared mainly by kidneys through both glomerular filtration and tubular secretion [7,8]. Nephrotoxicity caused by HDMTX arises from precipitation of MTX leading to crystal nephropathy [9] and direct toxic effect of MTX to renal tubules [10].…”

Delayed methotrexate clearance and acute kidney injury after high‐dose methotrexate chemotherapy concurrent with dasatinib in a patient with relapsed Philadelphia chromosome‐positive acute lymphoblastic leukemia: A case report

“…Her serum MTX level eventually normalized on day 17 after the start of HDMTX. No potentially interacting medications with MTX metabolism other than tyrosine kinase inhibitors (TKIs) were given for all three courses of HDMTX. The patient subsequently received an HLA‐6/8 matched cord blood transplantation that became successfully engrafted on day 16.…”