Prolongation of drug exposure in cerebrospinal fluid by encapsulation into DepoFoam.
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-beta-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 micrograms/ml (0.4 microM) 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.
Kim
S
S
Department of Medicine, UCSD Cancer Center, La Jolla 92093.
Khatibi
S
S
Howell
S B
SB
McCully
C
C
Balis
F M
FM
Poplack
D G
DG
D000818:Animals; D003561:Cytarabine / Q000008:administration & dosage / Q000134:cerebrospinal fluid*; D004337:Drug Carriers; D004339:Drug Compounding; D006207:Half-Life; D007278:Injections, Spinal; D008051:Lipid Bilayers; D008253:Macaca mulatta; D008297:Male
D004337:Drug Carriers; D008051:Lipid Bilayers; D003561:Cytarabine