Efficacy of glucarpidase (carboxypeptidase G2) in patients with acute kidney injury after high-dose methotrexate therapy

Brigitte C. Widemann, Stefan Schwartz, Nalini Jayaprakash, Robbin Christensen, Ching Hon Pui, Nikhil Chauhan, Claire Daugherty, Thomas R. King, Janet E. Rush, Scott Howard

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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.

Original languageEnglish (US)
Pages (from-to)427-439
Number of pages13
JournalPharmacotherapy
Volume34
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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gamma-Glutamyl Hydrolase
Acute Kidney Injury
Methotrexate
Kidney
Therapeutics
Osteosarcoma
Compassionate Use Trials
Serum
Clinical Protocols
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Terminology
Non-Hodgkin's Lymphoma

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)

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Efficacy of glucarpidase (carboxypeptidase G2) in patients with acute kidney injury after high-dose methotrexate therapy. / Widemann, Brigitte C.; Schwartz, Stefan; Jayaprakash, Nalini; Christensen, Robbin; Pui, Ching Hon; Chauhan, Nikhil; Daugherty, Claire; King, Thomas R.; Rush, Janet E.; Howard, Scott.

In: Pharmacotherapy, Vol. 34, No. 5, 01.01.2014, p. 427-439.

Research output: Contribution to journalArticle

Widemann, BC, Schwartz, S, Jayaprakash, N, Christensen, R, Pui, CH, Chauhan, N, Daugherty, C, King, TR, Rush, JE & Howard, S 2014, 'Efficacy of glucarpidase (carboxypeptidase G2) in patients with acute kidney injury after high-dose methotrexate therapy', Pharmacotherapy, vol. 34, no. 5, pp. 427-439. https://doi.org/10.1002/phar.1360
Widemann, Brigitte C. ; Schwartz, Stefan ; Jayaprakash, Nalini ; Christensen, Robbin ; Pui, Ching Hon ; Chauhan, Nikhil ; Daugherty, Claire ; King, Thomas R. ; Rush, Janet E. ; Howard, Scott. / Efficacy of glucarpidase (carboxypeptidase G2) in patients with acute kidney injury after high-dose methotrexate therapy. In: Pharmacotherapy. 2014 ; Vol. 34, No. 5. pp. 427-439.
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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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AU - Schwartz, Stefan

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AU - Christensen, Robbin

AU - Pui, Ching Hon

AU - Chauhan, Nikhil

AU - Daugherty, Claire

AU - King, Thomas R.

AU - Rush, Janet E.

AU - Howard, Scott

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N2 - 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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