Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Wahlestedt, Martin LU ; Hansson, Karin LU ; Bill, Alexandra ; Isaksson, Anders LU ; Heldrup, Jesper LU and Pronk, Cornelis Jan LU (2026) In Cancer Chemotherapy and Pharmacology 96(1).
Abstract

Purpose: 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. Methods: 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... (More)

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cancer, Folinic acid, Glucarpidase, High-dose methotrexate, Interaction, Rescue
in
Cancer Chemotherapy and Pharmacology
volume
96
issue
1
article number
45
publisher
Springer Science and Business Media B.V.
external identifiers
  • scopus:105038148907
  • pmid:42101491
ISSN
0344-5704
DOI
10.1007/s00280-026-04880-2
language
English
LU publication?
yes
id
d2cc85d1-56c8-4899-93d1-7e3c1ded3512
date added to LUP
2026-08-13 15:56:18
date last changed
2026-09-10 17:46:27
@article{d2cc85d1-56c8-4899-93d1-7e3c1ded3512,
  abstract     = {{<p>Purpose: 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. Methods: 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. Results: GP rapidly metabolized &gt; 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. Conclusion: 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.</p>}},
  author       = {{Wahlestedt, Martin and Hansson, Karin and Bill, Alexandra and Isaksson, Anders and Heldrup, Jesper and Pronk, Cornelis Jan}},
  issn         = {{0344-5704}},
  keywords     = {{Cancer; Folinic acid; Glucarpidase; High-dose methotrexate; Interaction; Rescue}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer Science and Business Media B.V.}},
  series       = {{Cancer Chemotherapy and Pharmacology}},
  title        = {{Glucarpidase efficacy in mitigating methotrexate toxicity is unaffected by concurrent administration of folinic acid}},
  url          = {{http://dx.doi.org/10.1007/s00280-026-04880-2}},
  doi          = {{10.1007/s00280-026-04880-2}},
  volume       = {{96}},
  year         = {{2026}},
}