PLASMA AND CEREBROSPINAL-FLUID PHARMACOKINETICS OF ACIVICIN IN OMMAYA RESERVOIR-BEARING RHESUS-MONKEYS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 66  (6) , 1333-1341
Abstract
Acivicin [an antineoplastic drug] was administered i.v. to rhesus monkeys bearing Ommaya reservoirs; serial blood and CSF samples were collected and analyzed to determine the time course of drug concentrations in these body fluids. After i.v. doses of 4 or 20 mg/kg (50 or 250 mg/m2), acivicin plasma concentrations demonstrated a rapid initial decline (distribution phase) and then declined exponentially with a terminal (elimination phase) half-life of 3-4 h. CSF concentrations increased over a period of 2-2.5 h, reaching peak values of 2.0-2.7 .mu.g/ml at 20 mg/kg and 0.3-0.5 .mu.g/ml at 4 mg/kg; thereafter, CSF levels declined in parallel with plasma with a CSF/plasma concentration ratio of 0.10-0.17. A 3-compartment pharmacokinetic model gave a close fit of predicted and observed plasma and CSF concentration data. Significant and predictable CSF penetration by i.v. administered acivicin in monkeys is consistent with observation of CNS side effects in patients in the phase I clinical trial and suggests that acivicin should be evaluated in the treatment of CNS malignancies and metastases.