High-dose methotrexate (HDMTX) is a common chemotherapy drug, but it can cause acute kidney injury and delayed MTX clearance, leading to toxicities. Glucarpidase is an enzyme used to break down MTX, but a new study suggests that half the recommended dose may be just as effective. The study, published in Journal of Cancer Research and Clinical Oncology, found that half-dose glucarpidase effectively lowered MTX levels in patients experiencing HDMTX-associated kidney injury, allowing for successful management with intensified folinic acid rescue.
Study Details
Researchers administered half-dose glucarpidase (mean 25 U/kg, range 17–32 U/kg) to seven patients with toxic MTX plasma concentrations following HDMTX therapy. MTX levels were measured using both immunological and liquid chromatography–mass spectrometry (LC–MS) methods. Toxicities were assessed using the National Cancer Institute—Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
All patients had HDMTX-associated kidney injury, with a median increase in creatinine levels of 251% within 48 hours after HDMTX initiation. Before glucarpidase, MTX plasma concentrations ranged from 3.1 to 182.4 μmol/L. The glucarpidase was administered 42–70 hours after HDMTX initiation.
Key Findings
Within one day of glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7%, resulting in levels of 0.02–2.03 μmol/L. MTX rebound was detected in plasma 42–73 hours after glucarpidase initiation, but concentrations remained below 10 μmol/L.
Implications of Half-Dose Glucarpidase
The study suggests that half-dose glucarpidase is effective in reducing MTX levels to concentrations manageable with intensified folinic acid rescue. This is particularly significant given the high cost of glucarpidase, as dose reduction strategies could substantially reduce the financial burden of treatment. According to the study, total cost savings in their cohort of seven patients were approximately $358,000.
Considerations for Clinical Practice
The researchers emphasize that while their findings support the use of lower glucarpidase doses, further dose-finding studies are needed. These studies should include pharmacokinetic analysis and assessment of clinical outcome measures to optimize glucarpidase dosing strategies. They also noted that intravenous glucarpidase treatment does not affect MTX levels within the cerebrospinal fluid, so half-dose glucarpidase is unlikely to improve symptoms of acute MTX-associated neurotoxicity.
Study Limitations
The authors noted that the assessment of Rapid and Sustained Clinically Important Reduction (RSCIR) was not possible in most patients, as MTX levels were not determined immediately before or right after glucarpidase injection by LC–MS. Additionally, the study was limited by its small sample size.
Conclusion
This study provides evidence that half-dose glucarpidase can effectively reduce toxic MTX levels in patients with HDMTX-associated kidney injury. The findings support the need for further research to refine glucarpidase dosing strategies and potentially reduce the economic burden of this essential rescue treatment.
