Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury

• DOI: 10.1007/s00280-021-04361-8
• Publication Date: 2021-10-20T17:56:55Z
• Authors: Sandra Heuschkel; Theresa Kretschmann; Raphael Teipel; Simone von Bonin; Stephan Richter; Susanne Quick; Nael Alakel; Christoph Röllig; Ekaterina Balaian; Frank Kroschinsky; Holger Knoth; Martin Bornhäuser; Malte von Bonin
• Keywords: Half-dose glucarpidase ; Female [MeSH] ; Aged [MeSH] ; High-dose methotrexate ; Adult [MeSH] ; Antimetabolites, Antineoplastic/adverse effects [MeSH] ; Humans [MeSH] ; Methotrexate plasma concentration ; Middle Aged [MeSH] ; Acute kidney injury ; Acute Kidney Injury/drug therapy [MeSH] ; Recombinant Proteins/administration ; Original Article ; Recombinant Proteins/therapeutic use [MeSH] ; Acute Kidney Injury/chemically induced [MeSH] ; Male [MeSH] ; gamma-Glutamyl Hydrolase/therapeutic use [MeSH] ; Antimetabolites, Antineoplastic/blood [MeSH] ; Acute Kidney Injury/blood [MeSH] ; gamma-Glutamyl Hydrolase/administration ; Methotrexate/blood [MeSH] ; Methotrexate/adverse effects [MeSH] ; Thrombocytopenia/chemically induced [MeSH] ; Folinic acid; Adult; Male; Antimetabolites, Antineoplastic; gamma-Glutamyl Hydrolase; Acute Kidney Injury; Middle Aged; Thrombocytopenia; Recombinant Proteins; 3. Good health; 03 medical and health sciences; Methotrexate; 0302 clinical medicine; Humans; Original Article; Female; Aged

Abstract Purpose High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels.

Methods Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17–32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography–mass spectrometry (LC–MS). Toxicities were assessed according to National Cancer Institute—Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Results All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80–455%) and showed toxic MTX plasma concentrations (range 3.1–182.4 µmol/L) before glucarpidase injection. The drug was administered 42–70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02–2.03 µmol/L. MTX rebound was detected in plasma 42–73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L.

Conclusion Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.