Toxicity and cerebrospinal fluid levels of carboplatin chronically infused into the brainstem of a primate

Purpose: Carboplatin was infused into the brainstem of cynomolgus monkeys to investigate neurotoxicity and systemic exposures following chronic local delivery. Methods: Infusions at 0.42 μl/h were intended to deliver 0.025 (n = 2), 0.075 (n = 3), 0.25 (n = 5), and 0.75 (n = 3) mg/kg by day 30. Laboratory tests, radiographic measurements, and clinical observations were used to monitor toxicity. Blood and cerebrospinal fluid (CSF) were sampled for platinum. Results: Lethargy and ataxia were observed after week 4 in the monkeys given 0.075 mg/kg, and week 2 in the monkeys given 0.25 mg/kg when the infused doses were ∼250 and 400 μg, respectively. Rapidly progressive neurotoxicity with the 0.75 mg/kg dose required termination of the infusions at days 4-10. Hematology and chemistry values were unremarkable in all groups. Blood levels of platinum remained undetectable in 0.025 and 0.075 mg/kg dose groups. Levels in the 0.25 mg/kg group were 3.1 ± 0.6 μg/l at 2 weeks and 5.2 ± 0.8 μg/l at 1 month. The CSF platinum levels varied. Animals in the 0.25 mg/kg group had higher CSF levels at 2 weeks (avg. 65 μg/l, range 36-89) compared to their 1 month value (avg. 60 μg/l, range 7-170), despite the constant infusion. Conclusion: Carboplatin can be chronically infused into monkey brainstems. Neurotoxicity is the predominant side effect and is dose-dependent. Pharmacokinetics of local and systemic delivery are different for carboplatin. Further studies are needed to monitor toxicity at higher flow rates and to investigate drug binding to abnormal central nervous system (CNS) tissues.