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Pharmacokinetics of Interstitial Delivery of Carmustine, 4-Hydroperoxycyclophosphamide, and Paclitaxel from a Biodegradable Polymer Implant in the Monkey Brain¹

School of Chemical Engineering, Cornell University, Ithaca, New York 14853 [L. K. F., W. M. S.]; Departments of Neurosurgery [M. G. E., A. S., E. P. S., R. T., M. W., H. B.] and Oncology [H. B.], The Johns Hopkins School of Medicine, Baltimore, Maryland 21287; and Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710 [O. M. C.]

Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [³H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28–41 µCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5–3.5 mM for carmustine, 0.3–0.4 mM for 4-HC, and 0.2–1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 µM for carmustine, 3 µM for 4-HC, and 0.6 µM for paclitaxel) concentrations were measured up to 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4–1200 times higher than that produced by i.v. administration of a higher dose.

¹ This study was supported by NIH Grant U01-CA52857 and was presented in part at the 87th Annual Meeting of the American Association for Cancer Research (Washington, DC) in 1995 and the First Scientific Meeting of the Society for Neuro-Oncology (Santa Fe, NM) in 1996.

² Recipients of the NIH National Research Service Award CA-09574.

³ Guilford Pharmaceuticals, Inc. provided partial funding for the study described in this paper. The Johns Hopkins University and H. B. will receive a share of sales royalties from Guilford, and they own Guilford stock, the sale of which is subject to certain restrictions under University policy. H. B. is also a consultant to Guilford, and Guilford has provided a gift for research in H. B.'s laboratory. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.

⁴ To whom requests for reprints should be addressed, at 120 Olin Hall, School of Chemical Engineering, Cornell University, Ithaca, NY 14853. E-mail: saltzman@cheme.cornell.edu.

Received 7/22/97. Accepted 12/12/97.

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