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Reply to: Glucarpidase for the Treatment of Methotrexate‐Induced Renal Dysfunction and Delayed Methotrexate Excretion

To the Editor:We are pleased that our paper has generated interest and happy to reply to the correspondence on the subject,[1] as it allows us to clarify the role of glucarpidase inmethotrexateinduced renal dysfunction and delayed methotrexate excretion. Methotrexate is primarily eliminated by the renal route and high-dosemethotrexate-induced renal toxicity is amedical emergency that requires immediate treatment to prevent further renal and nonrenal toxicity. In his correspondence, Dr. Meyers suggests that glucarpidase is unnecessary for the treatment of methotrexate-induced renal dysfunction, and that leucovorin alone should be used to manage these patients. It is true that leucovorin rescue is a required element following high-dose methotrexate administration. However, the ability of leucovorin to rescue cells from damage is concentration dependent. There are in vitro data demonstrating the inability of extracellular concentrations of leucovorin on the order of 1,000 umol/l to rescue cells exposed to methotrexate concentrations of 100 umol/l,[2] due to saturation of the active transport mechanism with high concentrations of methotrexate, and that sustained concentrations of even 10 umol/l methotrexate are difficult to rescue with clinically achievable concentrations of leucovorin. The use of glucarpidase can successfully lower methotrexate plasma concentrations from greater than 800 umol/l to a range that is manageable with the rescue agent leucovorin.[3] Additionally, Dr. Meyers suggests that glucarpidase is not useful due to the claim that it does not affect intracellular methotrexate concentrations. In fact, intracellular concentrations are highly related to plasma methotrexate concentrations.[4,5] In the setting of extremely high methotrexate plasma concentrations, pharmacokinetic data demonstrate that the decrease in systemic plasma concentrations of methotrexate caused by glucarpidase (more effectively) or hemodialysis (less effectively) in fact is followed by a temporary modest but real increase in plasma methotrexate concentrations,[6–8] due to redistribution of drug out of other tissue compartments. Thus, decreasing systemic concentrations of methotrexate will indeed cause a decrease in intracellular concentrations. This will also decrease the amount of methotrexate accumulating in the renal tubules and thus decrease the amount of urinary alkalinization that is required to protect renal tubules, thereby preventing additional renal insult. Being able to use the lower doses of leucovorin that are possible after glucarpidase administration may be advantageous. Because of the concerns of overrescuing tumor cells,[9] it is desirable to give enough leucovorin to minimize adverse effects on host tissue but not so much as to entirely negate the desired antitumor effect of methotrexate. Serious methotrexate toxicity and even deaths have been reported despite the use of glucarpidase, although in most of these cases, the use of glucarpidase was delayed 72–96 hr from the start of methotrexate.[3,8] Although we acknowledge that some of the serious toxicities/deaths were likely due at least partly to inadequate supportive care with hydration and leucovorin, the evidence is consistent with the notion that prolonged, high methotrexate concentrations may not be rescueable with leucovorin alone, and that early interventions to decrease systemic concentrations (with secondary decreases in intracellular concentrations) are critical to avoid severe toxicity. The point of our report on varying dosages of glucarpidase is for clinicians to consider administering glucarpidase even in cases when less than a full dosage of 50 U/kg is on hand; glucarpidase even at lower dosages is beneficial in preventing potentially lifethreatening adverse outcomes to high-dose methotrexate and should be considered in the armamentarium for treating patients with methotrexate-induced renal dysfunction.[10]