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Hematol Oncol. 2018 Apr;36(2):399-406. doi: 10.1002/hon.2479. Epub 2017 Oct 6.

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

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Hospices Civils de Lyon, Groupement Hospitalier Sud, Clinical Oncology Pharmacy Department, Pierre Bénite-EMR 3738, Université Lyon 1, Lyon, France.
Clinical Oncology Pharmacy Department, Groupement Hospitalier Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
Université Lyon 1, Lyon, France.
Groupement Hospitalier Sud, Department of Hematology, Hospices Civils de Lyon, Pierre-Bénite, France.
Centre Régional de Pharmacovigilance de Lyon, Lyon, France.


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/m2 ) 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.


antacid drugs; drug-drug interaction; methotrexate; proton-pump inhibitor; renal failure

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