Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model.
BACKGROUND
Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer), and the efficacy of Paclimer was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer in a canine dose escalation toxicity study to prepare its translation into clinical scenarios.


METHODS
Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer at 2-mg/kg (n=5), empty microspheres at 2-mg/kg (n=1), Paclimer at 20-mg/kg (n=5), or empty microspheres at 20-mg/kg (n=1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days 14-120. Paclitaxel concentrations were quantified by LC-MS.


RESULTS
Animals treated with 20-mg/kg Paclimer had minimal paclitaxel levels in plasma (range 0-7.84 ng/ml) and CSF (range 0-1.16 ng/ml). Animals treated with 2 mg/kg Paclimer had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60-120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus.


CONCLUSIONS
Paclimer-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.
Pradilla
Gustavo
G
Department of Neurosurgery, School of Medicine, The Johns Hopkins University, 725 N. Wolfe Street, Hunterian 817, Baltimore, MD 21205, USA.
Wang
Paul P
PP
Gabikian
Patrik
P
Li
Khan
K
Magee
Carolyn A
CA
Walter
Kevin A
KA
Brem
Henry
H
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000633:toxicity*; D001672:Biocompatible Materials; D001921:Brain; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D016503:Drug Delivery Systems; D008297:Male; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000633:toxicity*; D013534:Survival
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D017239:Paclitaxel