Use of Plasma Pharmacokinetics to Predict and Prevent Methotrexate Toxicity

Ronald G. Stoller, Kenneth R. Hande, Samuel A. Jacobs, Steven A. Rosenberg, Bruce A. Chabner

Research output: Contribution to journalArticlepeer-review

Abstract

To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48-hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean ±2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10–7 M. In seven patients with 48-hour concentrations above 9 X 10–7 M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue. (N Engl J Med 297:630–634, 1977) Methotraexate, an effective agent in treatment of leukemia, choriocarcinoma and other tumors, is one of the most versatile antineoplastic agents because its toxicity in high-dose regimens can be prevented by the reduced folate, leucovorin (5-formyltetrahydrofolate).1 High-dose methotrexate regimens (50 mg per kilogram or more) with leucovorin rescue have produced responses in metastatic osteogenic sarcoma2 and other tumors3 and have lengthened the relapse-free interval when used as an adjuvant after surgical excision of nonmetastatic osteogenic sarcoma.4 High-dose methotrexate therapy has not been without serious complications. Although the majority of such infusions cause only minor side effects, severe and prolonged myelosuppression and.

Original languageEnglish (US)
Pages (from-to)630-634
Number of pages5
JournalNew England Journal of Medicine
Volume297
Issue number12
DOIs
StatePublished - Sep 22 1977

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Use of Plasma Pharmacokinetics to Predict and Prevent Methotrexate Toxicity'. Together they form a unique fingerprint.

Cite this