CEREBROSPINAL-FLUID PHARMACOKINETICS AND TOXICOLOGY OF INTRAVENTRICULAR AND INTRATHECAL ARABINOSYL-5-AZACYTOSINE (FAZARABINE, NSC-281272) IN THE NONHUMAN PRIMATE

Arabinosyl-5-azacytosine (AAC), a new nucleoside antimetabolite, is br oadly active in preclinical tumor screening evaluations. To assess the potential for intrathecal use of this drug, we studied the toxicity a nd pharmacokinetics of intrathecal and intraventricular administration in nonhuman primates. Four adult male rhesus monkeys were given singl e 10 mg intrathecal (n = 1) or intraventricular (n = 3) doses of AAC t o determine its acute toxicity and pharmacokinetic parameters. An addi tional 3 animals were given four weekly 10 mg intrathecal doses to ass ess the systemic and neurologic toxicity associated with chronic admin istration. Disappearance from the cerebrospinal fluid (CSF) was biexpo nential, and CSF clearance was 0.2 ml/min, which exceeds the rate of C SF bulk flow by 5-fold. The peak CSF concentration and area under the concentration x time curve achieved with the intraventricular administ ration of 10 mg were one hundred, and fifty fold greater, respectively , than those achieved after an intravenous dose of 200 mg/kg (1500-240 0 mg) in prior experiments. No clinically evident neurotoxicity was ob served in either the single or the weekly x 4 dose groups. A slight, t ransient CSF pleocytosis and increased CSF protein was observed. Syste mic toxicity was limited to one animal in the weekly x 4 dose group wh o demonstrated a mild and transient decrease in his peripheral leukocy te count unassociated with a change in his hematocrit or platelet coun t. These studies in nonhuman primates demonstrate a clear pharmacokine tic advantage for intrathecal vs systemic administration of AAC. This is demonstrated by a 50-fold greater CSF drug exposure with an intrath ecal or intraventricular dose 1/200th of that which can be given syste mically. Intrathecal AAC was found to be safe on a weekly dosing sched ule. On the basis of these results, human trials evaluating intratheca l AAC are planned.