Extremely high levels of methotrexate can lead to precipitation of the drug in the renal tubules, delayed drug clearance, and the potential for acute renal failure. Preventing high-dose methotrexate toxicity requires effective methotrexate monitoring and knowledge of the appropriate protocols for leucovorin rescue and the role of glucarpidase, said Katherine Mandock, PharmD, BCPS, at the Hematology/Oncology Pharmacy Association 9th Annual Conference.
Methotrexate toxicity is a function of both the concentration of the drug and duration of exposure. Acute consequences of high concentrations (>5-10 µM) of methotrexate include severe renal and hepatic dysfunction. Sustained, elevated plasma levels of methotrexate (>0.1 µM) can lead to life-threatening myelosuppression and mucositis.
The first step to managing high-dose methotrexate administration (>1000 mg/m2 requiring leucovorin rescue) is to check for potential drug interactions, said Mandock, clinical oncology pharmacist at Smilow Cancer Hospital at Yale-New Haven, Connecticut. Weak organic acids (ie, nonsteroidal anti-inflammatory drugs) compete with methotrexate for tubular secretion, resulting in decreased renal clearance of methotrexate. High-dose vitamin C will acidify the urine and cause crystallization of methotrexate in the kidney, interfering with clearance. Proton pump inhibitors have been shown to cause methotrexate accumulation in the kidney.
Because methotrexate accumulates in third-space fluid, “in patients who have third-space fluid such as ascites or pleural effusion, you should think twice, if at all, about using high-dose methotrexate,” Mandock said.
Poor hydration or dehydration, a urine pH <6.5, decreased creatinine clearance, and third spacing are all risk factors for methotrexate toxicity. “When plasma concentrations of methotrexate are >10 to 100 µM, high doses of leucovorin are unlikely to completely reverse the toxicity of methotrexate, leading to ineffective leucovorin rescue,” she said.
To prevent high-dose methotrexate toxicity, the urine should be alkalinized via administration of sodium bicarbonate. “We keep the urine pH >7.5 because methotrexate and its metabolites are less soluble at lower urine pH’s,” Mandock reported.
To be effective, leucovorin rescue must be started within 24 to 48 hours of metho- trexate initiation, or within 24 hours of completion. It should be continued until the methotrexate level falls below 0.1 µM. The amount needed to reverse toxicity is proportional to the methotrexate concentration.
Essentials of Glucarpidase Rescue
Glucarpidase is a methotrexate antidote that was approved by the US Food and Drug Administration on January 17, 2012. It metabolizes circulating metho- trexate to 2,4-diamino-N10-methylpteroic acid (DAMPA). “In patients who have impaired renal function secondary to high levels of methotrexate, we’re now providing a nonrenal route of elimination for methotrexate in the form of DAMPA,” said Mandock.
It is indicated for the treatment of methotrexate concentrations >1 µmol/L (or plasma concentrations >2 standard deviations of the mean methotrexate concentration curve at least 12 hours following methotrexate administration) in patients with delayed methotrexate due to impaired renal function.
Plasma concentrations of methotrexate decrease by 99% on average within 15 minutes of glucarpidase administration. About 40% of patients given glucarpidase will experience a slight rebound in methotrexate concentrations, “but for most of these patients, the levels are decreased by >90% for a duration of 8 days,” she reported.
Glucarpidase will not reverse toxicities present prior to its administration, is most effective when given within 96 hours of methotrexate administration, and is not a substitute for leucovorin because glucarpidase does not gain entry into cells, Mandock cautioned. The schedule of leucovorin should be adjusted so that it is not administered 2 hours prior to or for 2 hours following glucarpidase. Other standard-of-care treatments (hydration, alkalization of urine) should be continued.
Serum levels interpretation should consider whether the laboratory uses high-performance liquid chromatography or immunoassays. Since glucarpidase converts circulating plasma methotrexate into DAMPA, and DAMPA interferes with the immunoassay measurement, use of immunoassays can result in methotrexate concentrations that are falsely elevated. “The half-life of DAMPA is 9 hours, so for 48 hours after the administration of glucarpidase, immunoassays are not reliable measures of methotrexate plasma concentrations,” she said.
“It’s also important that we base the leucovorin dose on pre-glucarpidase methotrexate levels for 48 hours post-glucarpidase” because leucovorin is a substrate for glucarpidase.
Mandock K. Monitoring methotrexate, leucovorin dose escalation, and the role of glucarpidase. Presented at: Hematology/Oncology Pharmacy Association 9th Annual Conference; March 20-23, 2013; Los Angeles, CA.