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Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model

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Summary

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 days14–120. 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 2mg/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.

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Authors and Affiliations

  1. Department of Neurosurgery, School of Medicine, The Johns Hopkins University, 725 N. Wolfe Street, Hunterian 817, Baltimore, 21205, MD, USA

    Gustavo Pradilla, Paul P. Wang, Patrik Gabikian, Khan Li & Henry Brem

  2. Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA

    Carolyn A. Magee

  3. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Kevin A. Walter

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  1. Gustavo Pradilla
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  2. Paul P. Wang
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  3. Patrik Gabikian
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  4. Khan Li
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  5. Carolyn A. Magee
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  6. Kevin A. Walter
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  7. Henry Brem
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Correspondence to Henry Brem.

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Pradilla, G., Wang, P.P., Gabikian, P. et al. Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model. J Neurooncol 76, 131–138 (2006). https://doi.org/10.1007/s11060-005-5531-z

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