The drug glucarpidase could serve as an antidote to kidney toxicity in patients receiving the chemotherapy agent methotrexate, according to a recent study published by Gupta et al in Blood.
Background
As a result of its ability to penetrate the blood-brain barrier, methotrexate is one of the most common chemotherapeutic agents used globally to treat cancers involving the central nervous system. However, high doses of methotrexate ≥ 500 g/m2 often cause severe complications such as acute kidney injury, liver toxicity, and neutropenia.
Glucarpidase is designed to rapidly clear methotrexate from the blood. The drug converts methotrexate in the blood into inactive metabolites within 15 minutes of its administration. Despite its potent biochemical effects, no study has examined whether these effects translate into clinical benefit. Because of this evidence gap, there is widespread variation in the use of glucarpidase.
“Glucarpidase is unique because it’s one of the very few potential antidotes available to counteract the high rates of toxicity caused by chemotherapy,” suggested lead study author Shruti Gupta, MD, Associate Physician in the Division of Renal Medicine at Brigham and Women’s Hospital and Director of Onconephrology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. “Even though glucarpidase was approved by the [U.S. Food and Drug Administration (FDA)] in 2012, our study is the first to provide a comprehensive assessment of its potential clinical benefits,” she added.
Study Methods and Results
In the study, investigators used the 2000 to 2022 data from 28 major U.S. cancer centers involving 708 patients with methotrexate-induced acute kidney injury—209 of whom received glucarpidase within 4 days following methotrexate exposure and 499 of whom did not—in order to mimic the conditions of a randomized clinical trial. This approach may help estimate the outcomes of a full clinical trial without the costs, timescale, and biases inherent in clinical trials, especially for relatively rare events in a specific patient population.
“Target trial emulation is a way to effectively analyze real-world data and to draw causal inferences from it, especially when clinical trials are unavailable and would be impractical to perform,” detailed senior study author David E. Leaf, MD, Director of Clinical and Translational Research in Acute Kidney Injury in the Division of Renal Medicine at Brigham and Women’s Hospital. “We worked with dozens of our collaborators across 28 sites to extract granular data from medical records—all by manual chart review—which allowed us to account for key variables in our models. This allowed us to have a high degree of confidence in our findings,” he noted.
The investigators then examined the association between treatment with glucarpidase and outcomes among patients with methotrexate-induced acute kidney injury. They compared kidney recovery between the two groups at the time of hospital discharge on the basis of changes in serum creatinine levels. The investigators also examined the speed of kidney recovery as well as the incidence of other adverse events such as liver toxicity and neutropenia.
The investigators found that the patients who received glucarpidase were more likely to experience kidney recovery compared with those who did not receive the treatment. For instance, glucarpidase treatment was associated with a 2.7-fold increase in the likelihood of kidney recovery compared with no glucarpidase treatment. Patients who received glucarpidase also had faster kidney recovery and a lower risk of severe neutropenia or liver toxicity compared with those who did not receive the drug.
Conclusions
The investigators hope that their findings can encourage physicans to use glucarpidase in patients with kidney toxicity from methotrexate.
“FDA approval is only the first step. If [patients] aren’t using the drug, then [they] aren’t benefiting from it,” underscored Dr. Leaf. “Our findings offer clinicians evidence-based data supporting glucarpidase,” he concluded.
Disclosure: The research in this study was funded by BTG International Inc. For full disclosures of the study authors, visit ashpublications.org.
