A 2017 guideline from an expert consensus group provides recommendations for use of glucarpidase in patients who develop high‐dose methotrexate (HDMTX)‐induced nephrotoxicity and delayed methotrexate excretion. The activity of glucarpidase on circulating MTX persists for 48 hours. However, rebound of plasma MTX can occur as the activity wanes and MTX redistributes to circulation from tissues. Therefore, if a second dose is considered, the guidelines recommend that glucarpidase should not be repeated within 48 hours of the first dose due to decreased efficacy. If urgent treatment is still needed, leucovorin rescue may be considered after 2 hours of the first glucarpidase dose. [1]
A 2014 pooled analysis of four compassionate-use trials evaluated glucarpidase in 476 patients with delayed methotrexate elimination due to acute kidney injury, of whom 169 were included in the efficacy analysis. Among these, 118 (69.8%) received a single dose of glucarpidase, 45 (26.6%) received a second dose, and 6 (3.6%) received a third dose. Median pre-glucarpidase plasma methotrexate concentration was 11.7 µmol/L, with a ≥95% reduction achieved in 136 (87%) of 156 patients at a median of 15 minutes post-glucarpidase. The median methotrexate concentration at each subsequent time point (15 minutes to day 8) was <0.54 µmol/L, corresponding to a ≥97% reduction. Rapid and sustained clinically important reduction (RSCIR) to ≤1 µmol/L was achieved in 83 of 140 patients (59%), with patients starting at concentrations ≥50 µmol/L less likely to achieve RSCIR. A second glucarpidase dose ≥48 hours after the first dose reduced methotrexate levels further in 8 patients, with reductions widely ranging from 8% to 97%. Additionally, renal recovery was assessed in 436 patients, with serum creatinine concentrations rising from a mean of 0.79 mg/dL pre-methotrexate to 2.79 mg/dL pre-glucarpidase and declining to a mean of 1.27 mg/dL by day 22 (n= 148). Furthermore, of 410 patients with CTCAE grade ≥2 renal impairment, 262 (63.9%) recovered to grade 0 or 1, with a median recovery time of 12.5 days. Overall, these data may indicate the potential for additional glucarpidase doses to contribute to methotrexate clearance in select cases, despite diminishing returns. [2]
A 2014 review assessed the effectiveness and safety of glucarpidase in managing delayed methotrexate clearance due to renal dysfunction in patients receiving high-dose methotrexate (HDMTX). The evaluation encompassed five non-randomized, prospective trials and one retrospective study and included patients with a serum creatinine increase of ≥50% from baseline or a creatinine clearance <60 mL/min. Overall, glucarpidase, administered as a single dose of 50 units/kg, demonstrated a >97% reduction in serum methotrexate concentrations (sMTX) within 15 minutes of administration across studies, as measured by high-performance liquid chromatography (HPLC). Yet this did not always translate to clinically meaningful outcomes as the results were inconsistently reported. One study reported glucarpidase doses given every 4 hours for 3 doses in the first 6 patients enrolled. It was discovered that there was no additional sMTX reduction with repeated doses so subsequent patients were defaulted to one dose of glucarpidase with the option of a second dose at least 24 hours after the first if sMTX levels were still elevated. Two patients received second doses of glucarpidase 4 and 5 days after the first dose. One had a reduction of sMTX from 4.2 to 1.6 μmol/L while the other had no reduction in sMTX. Overall, while glucarpidase is effective in drastically reducing sMTX in renal dysfunction, further randomized trials are warranted to assess its impact on long-term clinical benefits. [3]
A 2012 review of glucarpidase examined its use in patients with delayed methotrexate elimination due to renal dysfunction, including cases involving second doses. Across studies, patients with plasma methotrexate concentrations exceeding specific thresholds (e.g., >100 mcmol/L) were eligible for glucarpidase administration. In one single-arm, open-label study of 22 patients, 45% (95% confidence interval 27% to 65%) of patients achieved RSCIR in plasma methotrexate levels to ≤1 µmol/L after one dose. A second dose was given to patients with initial concentrations >100 µmol/L, but no additional patients achieved RSCIR. In another retrospective review of 1,141 patients, 22 required glucarpidase, with second doses administered to 28 patients due to persistently elevated levels, though further reductions were not observed. Similarly, in another trial involving 82 patients, 9 received a second dose, and one received a third, with methotrexate concentrations reduced by approximately 97% after the initial dose but limited additional reductions after subsequent doses. Overall, the findings suggested that the benefits of additional dosing were variable, with limited efficacy demonstrated beyond the first dose. [4]
A 2024 multicenter, open-label, phase II trial evaluated the use of glucarpidase for patients experiencing delayed MTX elimination after high-dose MTX therapy. This investigation comprised two studies: the CPG2-PII study and the OP-07-001 study. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively, in the two studies. In the CPG2-PII trial, patients with an MTX concentration ≥1 µmol/L, according to local laboratory results at 48 h after the first dose, could receive a second dose of 50 U/kg glucarpidase, whereas the OP-07-001 only allowed a single dose. The OP-07-001 study employed citric acid-treated blood samples to ensure the inactivation of glucarpidase during measurement, thus addressing potential overestimation artifacts noted in earlier trials. Results demonstrated that the rate of CIR, defined as plasma MTX levels below 1 µmol/L maintained for at least 5 days, was 76.9% (95% confidence interval [CI] 46.2 to 95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Despite rebound MTX concentrations observed after 48 hours, levels remained substantially lower than pretreatment values in most cases, confirming glucarpidase’s efficacy and tolerability for managing MTX toxicity in Japanese patients with delayed clearance. Of note, among four out of 13 patients in the CPG2-PII study administered a second dose, two achieved CIR (50.0%; 95%CI 6.8 to 93.2). The authors noted that while a second dose of glucarpidase may have clinical significance depending on initial MTX levels, its use should be carefully considered in light of drug costs, with popPK analysis and Bayesian MTX rebound estimation potentially aiding early decision-making. [5]