title: 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.
authors: Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892.
authors: C J
authors: CJ
authors: Allegra
authors: J
authors: J
authors: Jenkins
authors: R B
authors: RB
authors: Weiss
authors: F
authors: F
authors: Balis
authors: J C
authors: JC
authors: Drake
authors: J
authors: J
authors: Brooks
authors: R
authors: R
authors: Thomas
authors: G A
authors: GA
authors: Curt
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016597:Trimetrexate
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D016597:Trimetrexate