Plasma and cerebrospinal fluid pharmacokinetics of acivicin in Ommaya reservoir-bearing rhesus monkeys.

Acivicin was administered iv to rhesus monkeys bearing Ommaya reservoirs, and serial blood and cerebrospinal fluid (CSF) samples were collected and analyzed to determine the time course of drug concentrations in these body fluids. After iv 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 hrs. CSF concentrations increased over a period of 2--2.5 hrs, reaching peak values of 2.0--2.7 micrograms/ml at 20 mg/kg and 0.3--0.5 microgram/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 three-compartment pharmacokinetic model gave a close fit of predicted and observed plasma and CSF concentration data. Significant and predictable CSF penetration by iv 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.