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Clinical Pharmacology

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

^aMedizinische Klinik III, ^bInstitut für Klinische Chemie und Pathobiochemie, and ^cInstitut für Biometrie und Klinische Epidemiologie, Charité, Campus Benjamin Franklin, Berlin, Germany; ^dProtherics PLC, Runcorn, United Kingdom

Key Words. Carboxypeptidase G2 • Methotrexate • Toxicity • Kidney failure • Aged

Correspondence: Correspondence: Stefan Schwartz, M.D., Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Telephone: 49-30-8445-2337; Fax: 49-30-8445-4468; e-mail: stefan.schwartz{at}charite.de

Disclosure: S.S. has acted as a consultant for and received support from Protherics PLC. P.M. has acted as a consultant for Protherics PLC. T.A. is an employee of, owns stock in, and has received support from Protherics PLC. This study was supported in part by a research grant from Protherics PLC, Runcorn, UK.

Objective. Leucovorin and extracorporeal removal of methotrexate (MTX) have limited efficacy in delayed MTX elimination after high-dose methotrexate (HD-MTX) therapy. Glucarpidase (carboxypeptidase G2) cleaves MTX into nontoxic metabolites, but experience with this enzyme is limited in adult patients. We evaluated the effects of glucarpidase intervention in adult and elderly patients with delayed MTX elimination.

Patients and Methods. Forty-three patients (age, 18–78 years) with MTX serum concentrations (sMTX) of 1–1,187 µmol/l received glucarpidase, leucovorin rescue guided by MTX immunoassay, and standard supportive care. MTX and MTX metabolites were quantified in serum (24 patients) and urine (8 patients) by high-performance liquid chromatography. Contributory risk factors, toxicities, and survival were recorded in all patients.

Results. Glucarpidase was well tolerated and resulted in an immediate >97% reduction in sMTX, with a 0.2%–35% urinary recovery of the total MTX dose as inactive MTX metabolites. Forty (93%) of 43 patients had normalization (n = 25) or improvement (n = 15) of their serum creatinine. Frequent grade III–IV MTX toxicities were hematological (60%) and mucositis (35%); only eight (19%) patients developed grade III–IV nephrotoxicity. Ten (23%) of 43 patients experienced fatal complications associated with HD-MTX therapy. Patients with three or more contributory risk factors for delayed MTX elimination had a significantly poorer survival than patients with fewer than three risk factors (hazard ratio, 3.64; confidence interval, 1.14–17.54).

Conclusions. Glucarpidase is well tolerated and produces a rapid inactivation of substantial amounts of MTX. However, overall results are still unsatisfactory in adult and elderly patients, suggesting that earlier recognition of delayed MTX elimination and more rapid intervention are needed.