The use of glucarpidase as a rescue therapy for high dose methotrexate toxicity – a review of pharmacological and clinical data

ABSTRACT

Introduction

This review aims to summarize recent data on the pharmacodynamic, pharmacokinetic, and safety of glucarpidase. This is an enzymatic agent that catalyzes the conversion of methotrexate (MTX) into inactive metabolites. Glucarpidase is used to manage high-dose MTX (HDMTX) toxic plasma concentration, especially in patients with impaired renal function.

Areas covered

In this review, studies on glucarpidase clinical efficacy as a therapeutic option for patients suffering from MTX kidney toxicity were presented. Pharmacodynamic and pharmacokinetic properties of glucarpidase were included. Moreover, potential interactions and safety issues were discussed.

Expert opinion

The use of glucarpidase is an effective therapeutic strategy in both adults and children treated with high doses of MTX for various types of cancer who have developed acute renal failure. Glucarpidase causes MTX to be converted to nontoxic metabolites and accelerates the time for its complete elimination. After administration of glucarpidase, it is possible to resume HDMTX.

KEYWORDS:

• Glucarpidase
• HDMTX
• MTX
• MTX-induced nephrotoxicity
• pharmacokinetics

Article highlights

• Toxic plasma concentration of methotrexate (MTX) could lead to renal, digestive, and hematological complications.

• Kidney toxicity, one of the adverse events during high-dose MTX (HDMTX) therapy, can be overcome with glucarpidase, which converts MTX into inactive 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate, effectively reducing MTX concentration.

• Glucarpidase is approved for the treatment of patients with toxic plasma levels of MTX and its delayed elimination; however, no randomized clinical trials compared its clinical efficacy with other salvage therapies.

• It is considered that glucarpidase offers an extracellular rescue and does not clear intracellular reservoir of MTX, which can be observed as a post-glucarpidase MTX rebound. Leucovorin is an essential cellular rescue, but as a substrate for glucarpidase, these agents cannot be administered simultaneously.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received research funding and provided consultation for BTG Specialty Pharmaceuticals, the producer of glucarpidase. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.