PHASE-I EVALUATION AND PHARMACOKINETICS OF AZIRIDINYLBENZOQUINONE USING A WEEKLY INTRAVENOUS SCHEDULE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (8) , 3907-3911
Abstract
Quinone derivatives have shown intensive antitumor activity in a broad variety of neoplasias. Aziridinylbenzoquinone is designed to have adequate lipid solubility to attain useful drug concentrations in the CNS. A Phase I study of aziridinylbenzoquinone was conducted in 32 patients with advanced solid cancers. The drug was given as a slow i.v. injection on days 1, 8, 15 and 22 of a 42-day cycle with a 2-wk rest. Five dose levels ranging from 5-20 mg/m2 were studied, with 3-10 patients treated at each level; 156 doses were administered. The major toxicity was myelosuppression with the median nadir in platelet and white blood cells occurring at days 15-27 of the cycle, and first appearing at doses > 10 mg/m2. Anemia was first seen at the 10-mg/m2 dose level, occurring between days 22-40. Nonmyelosuppressive toxic effects included nausea and vomiting, anorexia, diarrhea, stomatitis, slight alopecia and transient fever. The highest tolerated dose was 20 mg/m2, the recommended dose for Phase II studies. Plasma and urine pharmacokinetics were studied in 17 patients by a high pressure liquid chromatography method. Plasma decay curves could be fitted to a 2-compartment open-system model with overall average .alpha. and .beta. half-life values of 10.5 .+-. 6.28 min and 16.90 .+-. 8.63 (SD) h, respectively. Aziridinylbenzoquinone levels were determined in urine samples of 12 patients, but < 0.1% of the dose was excreted in the 0- to 4-h sample of 2 patients, and none was detected in the urine of 10 patients.