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 broadly active in preclinical tumor screening evaluations. To assess the potential for intrathecal use of this drug, we studied the toxicity and pharmacokinetics of intrathecal and intraventricular administration in nonhuman primates. Four adult male rhesus monkeys were given single 10 mg intrathecal (n = 1) or intraventricular (n = 3) doses of AAC to determine its acute toxicity and pharmacokinetic parameters. An additional 3 animals were given four weekly 10 mg intrathecal doses to assess the systemic and neurologic toxicity associated with chronic administration. Disappearance from the cerebrospinal fluid (CSF) was biexponential, and CSF clearance was 0.2 ml/min, which exceeds the rate of CSF bulk flow by 5-fold. The peak CSF concentration and area under the concentration x time curve achieved with the intraventricular administration of 10 mg were one hundred, and fifty fold greater, respectively, than those achieved after an intravenous dose of 200 mg/kg (1500-2400 mg) in prior experiments. No clinically evident neurotoxicity was observed in either the single or the weekly x 4 dose groups. A slight, transient CSF pleocytosis and increased CSF protein was observed. Systemic toxicity was limited to one animal in the weekly x 4 dose group who demonstrated a mild and transient decrease in his peripheral leukocyte count unassociated with a change in his hematocrit or platelet count. These studies in nonhuman primates demonstrate a clear pharmacokinetic advantage for intrathecal vs systemic administration of AAC. This is demonstrated by a 50-fold greater CSF drug exposure with an intrathecal or intraventricular dose 1/200th of that which can be given systemically.(ABSTRACT TRUNCATED AT 250 WORDS)
Heideman
R L
RL
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
McCully
C
C
Balis
F M
FM
Poplack
D G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000633:toxicity*; D001374:Azacitidine / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000633:toxicity* / Q000031:analogs & derivatives; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008253:Macaca mulatta; D008297:Male
D000970:Antineoplastic Agents; C022121:fazarabine; D001374:Azacitidine