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Prolongation of Drug Exposure in Cerebrospinal Fluid by Encapsulation into DepoFoam¹

Division of Hematology/Oncology, Department of Medicine, UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093 [Si. K., Sh. K., S. B. H.], and the Pediatric Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892 [C. M., F. M. B., D. G. P.]

Prolonged maintenance of a therapeutic drug concentration in the cerebrospinal fluid is required for optimal treatment of leptomeningeal leukemia or carcinomatosis with cell cycle-specific antimetabolites. The pharmacokinetics of 1-ß-D-arabinofuranosylcytosine (ara-C) encapsulated into DepoFoam (Depo/Ara-C) was studied in six rhesus monkeys after intrathecal injection into the lumbar sac. Following a single 2-mg dose, the Depo/Ara-C concentration decreased biexponentially with initial and terminal half-lives of 14.6 and 156 h, respectively. The free drug concentration remained above the reported minimal cytotoxic level of 0.1 µg/ml (0.4 µM) for more than 672 h (28 days). In contrast, the half-life of ara-C following an intralumbar bolus dose of unencapsulated drug in a single animal was 0.74 h. A single intrathecal injection of Depo/Ara-C can maintain a therapeutic drug concentration in the cerebrospinal fluid for a very prolonged period.

¹ Supported in part by Grants CH-368 and CH-484 from American Cancer Society and Grants CA 23100 and 35309 from the NIH. This work was conducted in part by the Clayton Foundation for Research-California Division. S. B. H. is a Clayton Foundation investigator.

² To whom requests for reprints should be addressed.

Received 11/ 9/92. Accepted 1/26/93.

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