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.
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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)
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Copyright | © 2013 Pharmacotherapy Publications, Inc. |
Chemical References |
- Antimetabolites, Antineoplastic
- gamma-Glutamyl Hydrolase
- Leucovorin
- Methotrexate
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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)
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