PHARMACOKINETIC AND BIOCHEMICAL-STUDIES ON ACIVICIN IN PHASE-1 CLINICAL-TRIALS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (9) , 4460-4463
Abstract
Acivicin pharmacokinetics were studied in Phase I patients receiving i.v. treatment on single-dose or daily .times. 5 (daily times five doses) regimens repeated every 3 weeks. In 14 patients, the time course of plasma concentrations was characterized by a biexponential equation with a terminal (elimination-phase) half-life of 9.92 .+-. 3.91 h (mean .+-. SD), distribution phase half-life of 0.32 .+-. 0.28 h total body clearance of 1.69 .+-. 0.48 liters/h/m2, and volume of distribution of 21.79 .+-. 2.94 liters/m2. Acivicin kinetics appeared to be dose-independent over the range of 8.5-150 mg/m2/day. Urinary excretion of intact acivicin in nine patients ranged from 2-42% in the first 24 h following administration; interpatient variability in urinary excretion was large, but daily urinary recovery within patients on the daily .times. 5 schedule was quite consistent. Measurements of acivicin effects on the activity of carbamyl phosphate synthetase II (CPS II) were conducted using leukocytes and/or malignant ascites of three colon cancer patients. Acivicin given to one patient at 8.5 mg/m2/day on the daily .times. 5 schedule caused a 70% reduction in leukocyte CPS II activity within 5 h after therapy was initiated. Leukocyte CPS II activity remained suppressed at this level over the 5-day dosing regimen. In this patient, CPS II activity in malignant ascitic cells had decreased by 75% on day 4 of the daily .times. 5 regimen. On the single dose schedule, treatment of two patients with 100 mg/m2 caused leukocyte CPS II activity to decrease by > 90% within 4 h of treatment with gradual recovery over the next 2 days.