title: Treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase.
abstract: Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of glucarpidase, this drug is investigational and available only through compassionate use. Therefore, alternative treatments for methotrexate removal may be required. We describe a 13-year-old girl (body surface area 1.2 m(2)) with osteosarcoma who was treated with high-dose methotrexate 12 g/m(2) infused over 4 hours. Forty-eight hours after the infusion, her plasma methotrexate concentrations were elevated at 446 micromol/L. She exhibited severe signs of methotrexate toxicity, including encephalopathy, liver failure, and acute kidney injury, and could not tolerate conventional hemodialysis. Over the next 12 days, the patient was treated with continuous venovenous hemodialysis (CVVHD), single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase to enhance methotrexate elimination. Compared with standard CVVHD, SPAD did not significantly increase methotrexate removal as measured by elimination half-life and methotrexate saturation coefficient. The highest clearance rate among extracorporeal therapies was achieved by CVVHDF, with an effluent rate of 4950 ml/hour. The patient's clinical condition steadily improved, and all extracorporeal therapies were stopped 168 hours after methotrexate administration. The patient was discharged home and continued with chemotherapy, including methotrexate, which was dosed based on iothalamate glomerular filtration rates on the day before infusion. Although extracorporeal treatments appeared to enhance methotrexate clearance, the administration of glucarpidase resulted in the most rapid percentage decline (86%) in methotrexate concentration. Until glucarpidase is readily available, intermittent hemodialysis should be used to enhance methotrexate clearance. If the patient is unable to tolerate hemodialysis, use of CVVHDF with maximum effluent rates will enhance methotrexate clearance.
authors.affiliation: Department of Clinical, Social, and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A Mary
authors.initials: AM
authors.lastname: Vilay
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Mueller
authors.forename: Hilary
authors.initials: H
authors.lastname: Haines
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Alten
authors.forename: David J
authors.initials: DJ
authors.lastname: Askenazi
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000506:poisoning*; D057176:Compassionate Use Trials; D015507:Drugs, Investigational / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008727:Methotrexate / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000506:poisoning*; D012516:Osteosarcoma / Q000188:drug therapy*; D006435:Renal Dialysis / Q000379:methods; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D015507:Drugs, Investigational; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate