Glucarpidase, Leucovorin, and Thymidine for High-Dose Methotrexate-Induced Renal Dysfunction: Clinical and Pharmacologic Factors Affecting Outcome

Abstract

A B S T R A C T PurposeTo assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G 2 ), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. MethodsPatients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n ϭ 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (Ͼ 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre-and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. ResultsGlucarpidase was administered at a median of 96 hours (receiving thymidine, n ϭ 44) and 66 hours (not receiving thymidine, n ϭ 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. ConclusionEarly intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function

“…Ten patients (23%) died due to complications associated with high-dose methotrexate, and 9 (21%) died due to disease progression. 4 In 2010, Widemann et al 8 conducted a study examining the role of glucarpidase in the management of patients with high-dose methotrexate-induced nephrotoxicity. The study included 100 patients with a median age of 17 years who received glucarpidase at a median of 96 hours from the start of methotrexate infusion.…”

“…In comparison to plasma exchanges and peritoneal dialysis, hemodialysis-based strategies have been demonstrated to produce increased reductions in serum methotrexate concentrations (reductions of up to 50-70% from baseline) and contribute to full recovery of renal function. 4,[7][8][9] In addition to dialysis-based approaches, the treatment of methotrexate-induced nephrotoxicity may involve the use of glucarpidase (also known as carboxypeptidase G2), a recombinant bacterial enzyme that cleaves methotrexate into inactive metabolites. 10 Glucarpidase has been available for compassionate use in the United States since 1993 and was approved in 2012 (as Voraxaze, BTG International Ltd.) by the Food and Drug Administration (FDA) for the treatment of serum methotrexate concentrations greater than 1 mM/L in patients with delayed methotrexate clearance due to impaired renal function, typically defined as a creatinine clearance of less than 60 mL/min.…”

Methotrexate Overdose

“…By providing reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate, citrovorum factor) to bypass the metabolic block induced by methotrexate, within 24 to 36 hours after administration of methotrexate, normal cells that have not already had lethal DNA damage can be rescued [3,4].…”

Odnos Ph I Aktivnosti Enzima Alanin Aminopeptidaze I Gama-Glutamiltransferaze U Urinu Pacijenata Tretiranih Metotreksatom

“…Metotreksat se primjenjuje u visokim, srednjim i niskim dozam a najčešće intravenski (6).Visoke doze od 500 ili više mg/m 2 se primjenjuju u slučajevima leukemije, limfoma, leptomeningealnih metastaza i osteosarkoma. Srednje doze metotreksata, od 50 do 500 mg/m 2 , se primjenjuju u slučajevima gestacionih tropoblastičnih bolesti, a niske doze od 50 ili manje mg/m 2 se primjenjuju u antiinflamatornoj terapiji reumatoidnog artritisa i psorijaze (7,8).…”