Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy.

Abstract

STUDY OBJECTIVE:

Because the incidence rate of renal impairment is 2-10% for patients treated 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 to 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 weeks-84 years). Osteosarcoma (36%), non-Hodgkin 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 minutes) through the last (median 40 hours) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. A total of 64% 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.

• Authors: Brigitte C Widemann, Stefan Schwartz, Nalini Jayaprakash, Robbin Christensen, Ching-Hon Pui, Nikhil Chauhan, Claire Daugherty, Thomas R King, Janet E Rush, Scott C Howard
• Journal: Pharmacotherapy (Pharmacotherapy) Vol. 34 Issue 5 Pg. 427-39 (May 2014) ISSN: 1875-9114 [Electronic] United States
• PMID: 24132809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Pharmacotherapy Publications, Inc.

Chemical References

• Antimetabolites, Antineoplastic
• gamma-Glutamyl Hydrolase
• Leucovorin
• Methotrexate

Topics

• Acute Kidney Injury (blood, chemically induced, prevention & control)
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects, blood, therapeutic use)
• Bone Neoplasms (blood, complications, drug therapy)
• Compassionate Use Trials
• Drug Administration Schedule
• Humans
• Leucovorin (administration & dosage, therapeutic use)
• Methotrexate (administration & dosage, adverse effects, blood, therapeutic use)
• Osteosarcoma (blood, complications, drug therapy)
• Treatment Outcome
• gamma-Glutamyl Hydrolase (administration & dosage, therapeutic use)