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Depocyt (Cytarabine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

DepoCyt® (cytarabine liposome injection) is a sterile, injectable suspension of the antimetabolite cytarabine, for intrathecal administration. The chemical name of cytarabine is 4-amino-1 -β-D-arabinofuranosyl-2(1H)-pyrimidinone, and is also known as cytosine arabinoside. It has a molecular formula of C9H13N3O5, and a molecular weight 243.22 g/mol. Cytarabine has the following structural formula:

DepoCyt is available as a single-dose vial containing 50 mg/5 mL (10 mg/mL) of cytarabine. DepoCyt is formulated as a sterile, non-pyrogenic, white to off-white suspension of cytarabine liposomes in 0.9% w/v sodium chloride in water for injection. Each mL contains 10 mg cytarabine, 4.4 mg cholesterol, 1.2 mg triolein, 5.7 mg dioleoylphosphatidylcholine (DOPC), and 1.0 mg dipalmitoylphosphatidylglycerol (DPPG). DepoCyt is preservative-free. The pH of the product falls within the range from 5.5 to 8.5.

Liposome drug products may behave differently from nonliposome drug products. DepoCyt (cytarabine liposome injection) is not equivalent to, and cannot be substituted for, other drug products containing cytarabine.

CLINICAL PHARMACOLOGY

Mechanism of Action

DepoCyt® (cytarabine liposome injection) is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.

Pharmacokinetics

Following intrathecal administration of DepoCyt 50 mg, peak levels of free CSF cytarabine were observed within 1 hour of dosing and ranged from 30 to 50 mcg/mL. The terminal half-life for the free CSF cytarabine ranged from of 5.9 to 82.4 hours. Systemic exposure to cytarabine was negligible following intrathecal administration of DepoCyt 50 mg.

Metabolism and Elimination

The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U. In contrast to systemically administered cytarabine, which is rapidly metabolized to ara-U, conversion to ara-U in the CSF is negligible after intrathecal administration because of the significantly lower cytidine deaminase activity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulk flow rate of 0.24 mL/min.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with DepoCyt.

Cytarabine was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and SCE in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent bone marrow, mouse micronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in vitro.

No studies assessing the impact of cytarabine on fertility are available in the literature. Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations occurred in mice given IP cytarabine. Because the systemic exposure to free cytarabine following intrathecal treatment with DepoCyt was negligible, the risk of impaired fertility after intrathecal DepoCyt is likely to be low.

CLINICAL STUDIES

DepoCyt® (cytarabine liposome injection) was studied in 2 controlled clinical studies that enrolled patients with neoplastic meningitis.

Study 1 – Solid Tumors, Lymphoma, or Leukemia

The first study, which was a randomized, multi-center, multi-arm study involving a total of 99 treated patients, compared 50 mg of DepoCyt administered every 2 weeks to standard intrathecal chemotherapy administered twice a week to patients with solid tumors, lymphoma, or leukemia. For patients with lymphoma, standard therapy consisted of 50 mg of unencapsulated cytarabine given twice a week. Thirty-three lymphoma patients (17 DepoCyt, 16 cytarabine) were treated. Patients went off study if they had not achieved a complete response defined as clearing of the CSF from all previously positive sites in the absence of progression of neurological symptoms, after 4 weeks of treatment with study drug.

In the first study, complete response was prospectively defined as (1) conversion, confirmed by a blinded central pathologist, from a positive examination of the CSF for malignant cells to a negative examination on two separate occasions (at least 3 days apart, on day 29 and later) at all initially positive sites, together with (2) an absence of neurological progression during the treatment period.

The complete response rates in the first study of lymphoma are shown in Table 3. Although there was a plan for central pathology review of the data, in 4 of the 7 responding patients on the DepoCyt arm this was not accomplished and these cases were considered to have had a complete response based on the reading of an unblinded pathologist. The median overall survival of all treated patients was 99.5 days in the DepoCyt group and 63 days in the cytarabine group. In both groups the majority of patients died from progressive systemic disease, not neoplastic meningitis.

Study 2 – Lymphoma

The second study was a randomized, multi-center, multi-arm study involving a total of 124 treated patients with either solid tumors or lymphomas. In this study, 24 patients with lymphoma were randomized and treated with DepoCyt or cytarabine. Patients received 6 two-week induction cycles of DepoCyt 50 mg every 2 weeks or cytarabine 50 mg twice weekly. Patients then received four maintenance cycles of DepoCyt 50 mg every 4 weeks, or cytarabine 50 mg weekly for 4 weeks. In both studies, patients received concurrent treatment with dexamethasone to minimize symptoms associated with chemical arachnoiditis [see Warnings and Precautions (5) and Dosage and Administration (2)]. In this study, cytological response was assessed in a blinded fashion utilizing a similar definition as in the first study. The results in patients with lymphomatous meningitis are shown in Table 3.

Table 3: Complete Cytological Responses in Patients with Lymphomatous Meningitis
DepoCyt® Cytarabine
Study 1
95% CI
7/17 (41%)
(18%, 67%)
1/16 (6%)
(0%, 30%)
Study 2
95% CI
4/12 (33%)
(10%, 65%)
2/12 (17%)
(2%, 48%)

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