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A phase I and pharmacokinetic study of trimetrexate using a 24-hour continuous-injection schedule.

Abstract：

:Trimetrexate (TMTX) is an analog of methotrexate and a potent inhibitor of the enzyme dihydrofolate reductase. In this phase I study, TMTX was given intravenously to 32 patients as a constant infusion over 24 hours every 28 days. The maximum-tolerated dose of TMTX was 200 mg/m2, with myelosuppression as the dose-limiting toxicity. Other toxicities included nausea and vomiting, stomatitis, erythema and phlebitis at the site of infusion, rash and skin hyperpigmentation, and elevated serum hepatic enzymes. Two drug-related deaths occurred secondary to leukopenia and sepsis. Twenty-six patients were evaluable for antitumor response. Twenty-one patients had progressive disease, while three patients had disease stabilization. There were two partial responses observed--one in a patient with breast cancer and a second in a patient with nasopharyngeal carcinoma. TMTX pharmacokinetics were studied in 15 patients. The drug had a mean terminal half-life of 13 hours. Steady-state was not achieved during the 24-hour infusions. Only 6% of the parent compound was excreted unchanged in the urine, and CSF levels averaged less than 2% of simultaneously measured plasma levels. A dose of 150 mg/m2 is recommended for phase II trials of TMTX using this 24-hour infusion schedule.

journal_name

Invest New Drugs

journal_title

Investigational new drugs

authors

Allegra CJ,Jenkins J,Weiss RB,Balis F,Drake JC,Brooks J,Thomas R,Curt GA

doi

10.1007/BF00177251

subject

Has Abstract

pub_date

1990-05-01 00:00:00

pages

159-66

issue

2

eissn

0167-6997

issn

1573-0646

journal_volume

8

pub_type

杂志文章

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