A pharmacokinetic study of intra-CSF administered encapsulated cytarabine (DepoCyt®) for the treatment of neoplastic meningitis in patients with leukemia, lymphoma, or solid tumors as part of a phase III study
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Cytarabine liposome injection (DepoCyt®), a sterile suspension of the antimetabolite cytarabine, encapsulated into multivesicular, lipid-based particles, has been developed to improve the treatment of neoplastic meningitis (NM) through sustained release of cytarabine. The objective of this study was to determine the pharmacokinetics (PK) of cytarabine after intrathecal administration of 50 mg encapsulated cytarabine (DepoCyt®) in patients with neoplastic meningitis up to 336 h (14 days) after dosing.
This was an open-label study wherein two 50-mg doses of DepoCyt® were administered 14 days apart via the intraventricular (IVT) route or by lumbar puncture (LP). Cerebrospinal fluid (CSF) samples were collected from eight adult patients at various times up to 14 days after each dose. Plasma samples were also collected within the same time period. CSF samples were analyzed for unencapsulated (free) and encapsulated cytarabine and the cytarabine metabolite, ara-U. Plasma samples were analyzed for free cytarabine and ara-U. The limit of detection was 0.003 μg/mL cytarabine and 0.016 μg/ml for ara-U.
The concentration of free and encapsulated cytarabine in the ventricular and lumbar CSF ranged from 0.01 to 1500 μg/mL and were detectable up to 14 days post-dosing. Free cytarabine concentrations in plasma were only sporadically detectable. CSF and plasma concentrations of ara-U were low in all samples.
The administration of intrathecal encapsulation cytarabine prolongs sustained tumor exposure to cytotoxic concentrations of cytarabine (>0.02 µg/ml) with a slow continuous release of cytarabine from the DepoFoamTM particles, so drug exposure is prolonged over time, resulting in lower peak cytarabine levels and a longer duration of exposure compared with standard cytarabine (Ara-C).
KeywordsEncapsulated cytarabine DepoCyt® Ara-C Cytosine arabinoside Neoplastic meningitis Pharmacokinetics
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Surasak Phuphanich, MD was supported in part by a Georgia Cancer Coalition Distinguished Clinical Investigator Professorial Award. We gratefully acknowledge the excellent editing assistance of Ms. Melissa Phuphanich.
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