Central Nervous System Toxicity and Cerebrospinal Fluid Pharmacokinetics of Intraventricularly Administered Bleomycin in Beagles¹

The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [³H]Inulin was used as a reference compound. Both [³H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a “minimally toxic” dose of bleomycin (approximately 0.1 mg/week) produces a CSF C × t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.