Abstract | INTRODUCTION:
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.
|
Authors | Gustavo Pradilla, Paul P Wang, Patrik Gabikian, Khan Li, Carolyn A Magee, Kevin A Walter, Henry Brem |
Journal | Journal of neuro-oncology
(J Neurooncol)
Vol. 76
Issue 2
Pg. 131-8
(Jan 2006)
ISSN: 0167-594X [Print] United States |
PMID | 16284923
(Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
|
Chemical References |
- Antineoplastic Agents, Phytogenic
- Biocompatible Materials
- Paclitaxel
|
Topics |
- Animals
- Antineoplastic Agents, Phytogenic
(administration & dosage, cerebrospinal fluid, toxicity)
- Biocompatible Materials
- Brain
- Chemistry, Pharmaceutical
- Dogs
- Drug Delivery Systems
- Male
- Microspheres
- Paclitaxel
(administration & dosage, cerebrospinal fluid, toxicity)
- Survival
|