|
|
Toxicity and Cerebrospinal Fluid Levels
of Carboplatin Chronically Infused into the Brainstem of a Primate
R.J. Strege, Y.J. Liu, A.
Kiely, R.M. Johnson, E.M. Gillis, P. Storm, B.S. Carson, G.I. Jallo, M. Guarnieri
Division
of Pediatric Neurosurgery, Johns Hopkins School of Medicine, Baltimore MD, USA;
Present address: Klinicum Plau am See, Germany [R.J.S., Y.J.L., A.K., B.S.C.,
G.I.J., M.G.]; DURECT Corporation,
Cupertino, CA, USA [R.M.J., E.M.G.]; Division of Pediatric Neurosurgery, Johns Hopkins
School of Medicine, Baltimore MD, USA [P.S.].
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.
Keywords: brain tumor, brainstem, carboplatin, intratumoral drug delivery, local
therapy, primate, toxicity
Copyright
©
2004 Kluwer Academic Publishers.
All rights reserved
Source: doi:10.1023/B:NEON.0000024243.31886.ab
|
