Efficacy of Glucarpidase (Carboxypeptidase G2) in Patients with Acute Kidney Injury After High‐Dose Methotrexate Therapy

Abstract

STUDY OBJECTIVE As the incidence rate of renal impairment is 2–10% for patients treatment with high-dose methotrexate , and renal impairment develops in 0–12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination. DESIGN Pooled analysis of efficacy data from four multicenter, single-arm, compassionate-use clinical trials using protocols from 1993–2007. PATIENTS Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1 µmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement. MEASUREMENTS AND MAIN RESULTS Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1 µmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20 years (range 5 wks–84 yrs). Osteosarcoma (36%), non-Hodgkin’s lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7 µmol/L. At the first (median 15 min) through the last (median 40 hrs) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. Sixty-four percent of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5 days after glucarpidase administration. CONCLUSION Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients.

Effects of silymarin on methotrexate-induced nephrotoxicity in rats

“…MTX is one of the most widely used anticancer drugs and administration of high-dose MTX is an important component in the treatment of a variety of childhood and adult cancers. 30,31 MTX-induced nephrotoxicity continues to occur despite the preventive measures such as administration of pharmacokinetically guided leucovorin, urinary alkalinization and intravenous hydration. 31,32 MTX-induced renal toxicity can be life threatening because, it further leads to delayed elimination of MTX, and the resulting sustained, elevated circulating MTX level may lead to the development of other MTX-related toxicities.…”

“…30,31 MTX-induced nephrotoxicity continues to occur despite the preventive measures such as administration of pharmacokinetically guided leucovorin, urinary alkalinization and intravenous hydration. 31,32 MTX-induced renal toxicity can be life threatening because, it further leads to delayed elimination of MTX, and the resulting sustained, elevated circulating MTX level may lead to the development of other MTX-related toxicities. 30,32 Treatment approaches including dialysis-based methods to remove MTX have limited effectiveness.…”

Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function

“…5 In two open-label, multicenter trials involving a total of 290 patients, the most common glucarpidase-associated adverse reactions included paresthesia (2%), flushing (2%), nausea (2%), vomiting (2%), hypotension (1%), and headache (1%). 15 All but one reaction were grade 1 or 2 adverse events, and patients recovered without intervention. One patient experienced grade 3 flushing.…”

“…15 However, a substantial minority of patients died due to methotrexate toxicity despite glucarpidase therapy. Mortality rates in the four clinical trials ranged from 0 to 23% (Table 1), and all trials allowed concurrent dialysis, potentially confounding the effect of glucarpidase on mortality and suggesting that there are currently no interventions that can prevent deaths related to methotrexate toxicity.…”

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

“…In cases of severely delayed elimination of methotrexate, less than half of the protocols include guidelines for the use of carboxypeptidase that enzymatically breaks down methotrexate to non-toxic metabolites. 24 Because of the very strong association between renal impairment and delayed methotrexate clearance, both parameters were included in the consensus defi nition.…”