Co-administration of High-Dose Methotrexate with a Proton Pump Inhibitor in Primary Central Nervous System Lymphoma with Recent Upper Gastrointestinal Bleed: A Case Report and Literature Review.

Abstract

Concomitant use of interacting drugs with high-dose methotrexate (HD-MTX) may cause delay in methotrexate (MTX) clearance. Prolonged exposure to toxic MTX concentrations increases the risk of adverse events.  A 28-year-old man with primary central nervous system lymphoma and recent upper gastrointestinal bleed received HD-MTX (2,500 mg/m²) as part of the DeAngelis protocol. Early intervention by discontinuing a precipitating drug (piperacillin-tazobactam) and substituting it with cefepime minimised the risk of delayed clearance. Serum MTX monitoring at 24 hours was performed for early optimisation of leucovorin rescue dose. In cycle 1, serum MTX was 3.6 μmol/L at 24 hours, <0.3 μmol/L at 48 hours, and <0.3 μmol/L at 72 hours; in cycle 2, it was 1.5 μmol/L, 0.5 μmol/L, and <0.3 μmol/L, respectively. The 72-hour result was below the reportable limit of the assay (0.3 μmol/L), so the target of <0.1 μmol/L could not be verified. No MTX toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or above was documented. Several studies report a significant drug-drug interaction between MTX and proton pump inhibitors. However, this single case does not establish the safety of co-administration. The outcome may reflect preserved renal function, hydration, urine alkalinisation, leucovorin rescue, and close monitoring rather than the absence of interaction. When concurrent administration is considered necessary, earlier preventive strategies and monitoring may be instituted for early detection of delayed MTX clearance.