Glucarpidase efficacy in mitigating methotrexate toxicity is unaffected by concurrent administration of folinic acid

High-dose methotrexate (HDMTX) is a cornerstone in pediatric oncology, but delayed methotrexate elimination (DME) can cause severe toxicity. Rescue therapy typically combines folinic acid (FA) and glucarpidase (GP), yet current guidelines recommend pausing FA around GP administration due to presumed interference. This study aimed to determine whether FA affects GP efficacy in metabolizing methotrexate and to assess the impact on folate metabolites.

An ex vivo model was developed using human plasma spiked with clinically relevant concentrations of methotrexate and FA, with or without GP. Samples were analyzed by mass spectrometry to quantify methotrexate, FA, and related metabolites. Additional experiments included blood from pediatric patients receiving HDMTX per ALLTogether protocol.

GP rapidly metabolized > 99% of methotrexate across all tested conditions, regardless of FA presence, producing robust DAMPA levels. FA degradation by GP was observed at varying levels, ranging from 8 to 78%. Patient samples confirmed efficient methotrexate clearance by GP, with similar DAMPA production whether FA was present or absent.

Concurrent FA administration does not compromise GP efficacy in neutralizing methotrexate. These findings challenge current recommendations to suspend FA around GP dosing and suggest that continuous FA rescue may be safe and beneficial. Adjustments to FA dosing post-GP may be warranted due to partial FA degradation. Further clinical studies should refine rescue strategies to optimize efficacy and minimize toxicity.