Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Pacira Limited, Wessex House, Marlow Road, Bourne End, Buckinghamshire, SL8 5SP, United Kingdom
Pharmacotherapeutic group: Antimetabolites, pyrimidine analogues
ATC code: L01BC01
DepoCyte is a sustained-release formulation of 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 synthesis. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture.
For cell-cycle phase specific antimetabolites the duration of exposure of neoplastic cells to cytotoxic concentrations is an important determination of efficacy.
In vitro studies, examining more than 60 cell lines, demonstrated that the median cytarabine concentration resulting in 50% growth inhibition (IC50) was approximately 10 μM (2.4 μg/ml) for two days of exposure and 0.1 μM (0.024 μg/ml) for 6 days of exposure. The studies also demonstrated susceptibility of many solid tumour cell lines to cytarabine, particularly after longer periods of exposure to cytarabine.
In an open-label, active-controlled, multicentre clinical study, 35 patients with lymphomatous meningitis (with malignant cells found on CSF cytology) were randomised to intrathecal therapy with either DepoCyte (n=18) or unencapsulated cytarabine (n=17). During the 1 month Induction phase of treatment, DepoCyte was administered intrathecally as 50 mg every 2 weeks, and unencapsulated cytarabine as 50 mg twice a week. Patients who did not respond discontinued protocol treatment after 4 weeks. Patients who achieved a response (defined as clearing of the CSF of malignant cells in the absence of progression of neurological symptoms) went on to receive Consolidation and Maintenance therapy for up to 29 weeks.
Responses were observed in 13/18 (72%, 95% confidence intervals: 47, 90) of DepoCyte patients versus 3/17 (18% patients, 95% confidence intervals: 4, 43) in the unencapsulated cytarabine arm. A statistically significant association between treatment and response was observed (Fisher’s exact test p-value = 0.002). The majority of DepoCyte patients went on beyond Induction to receive additional therapy. DepoCyte patients received a median of 5 cycles (doses) per patient (range 1 to 10 doses) with a median time on therapy of 90 days (range 1 to 207 days).
No statistically significant differences were noted in secondary endpoints such as duration of response, progression-free survival, neurological signs and symptoms, Karnofsky performance status, quality of life and overall survival. Median progression-free survival (defined as time to neurological progression or death) for all treated patients was 77 versus 48 days for DepoCyte versus unencapsulated cytarabine, respectively. The proportion of patients alive at 12 months was 24% for DepoCyte versus 19% for unencapsulated cytarabine.
In an open-label non-comparative dose escalation study in 18 paediatric patients (4 to 19 years) with leukaemic meningitis or neoplastic meningitis due to primary brain tumour, an intrathecal dose of 35 mg was identified as the maximum tolerated dose.
Analysis of the available pharmacokinetic data shows that following intrathecal DepoCyte administration in patients, either via the lumbar sac or by intraventricular reservoir, peaks of free cytarabine were observed within 5 hours in both the ventricle and lumbar sac. These peaks were followed by a biphasic elimination profile consisting of an initial sharp decline and subsequent slow decline with a terminal phase half-life of 100 to 263 hours over a dose-range of 12.5 mg to 75 mg. In contrast, intrathecal administration of 30 mg free cytarabine has shown a biphasic CSF concentration profile with a terminal phase half-life of about 3.4 hours.
Pharmacokinetic parameters of DepoCyte (75 mg) in neoplastic meningitis patients in whom the medicinal product was administered either intraventricularly or by lumbar puncture suggest that exposure to the active substance in the ventricular or lumbar spaces is similar regardless of the route of administration. In addition, compared with free cytarabine, the formulation increases the biological half-life by a factor of 27 to 71 depending upon the route of administration and the compartment sampled. Encapsulated cytarabine concentrations and the counts of the lipid particles in which the cytarabine is encapsulated in followed a similar distribution pattern. AUCs of free and encapsulated cytarabine after ventricular injection of DepoCyte appeared to increase linearly with increasing dose, indicating that the release of cytarabine from DepoCyte and the pharmacokinetics of cytarabine are linear in human CSF.
The transfer rate of cytarabine from CSF to plasma is slow and the conversion to uracil arabinoside (ara-U), the inactive metabolite, in the plasma is fast. Systemic exposure to cytarabine was determined to be negligible following intrathecal administration of 50 mg and 75 mg of DepoCyte.
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, (1-β-Darabinofuranosyluracil or uracil arabinoside) followed by urinary excretion of ara-U. In contrast with systemically administered cytarabine which is rapidly metabolised 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.
The distribution and clearance of cytarabine and of the predominant phospholipid component of the lipid particle (DOPC) following intrathecal administration of DepoCyte was evaluated in rodents. Radiolabels for cytarabine and DOPC were distributed rapidly throughout the neuraxis. More than 90% of cytarabine was excreted by day 4 and an additional 2.7% by 21 days. The results suggest that the lipid components undergo hydrolysis and are largely incorporated in the tissues following breakdown in the intrathecal space.
A review of the toxicological data available for the constituent lipids (DOPC and DPPG) or similar phospholipids to those in DepoCyte indicates that such lipids are well tolerated in various animal species even when administered for prolonged periods at doses in the g/kg range.
The results of acute and subacute toxicity studies performed in monkeys suggested that intrathecal DepoCyte was tolerated up to a dose of 10 mg (comparable to a human dose of 100 mg). Slight to moderate inflammation of the meninges in the spinal cord and brain and/or astrocytic activation were observed in animals receiving intrathecal DepoCyte. These changes were believed to be consistent with the toxic effects of other intrathecal agents such as unencapsulated cytarabine. Similar changes (generally described as minimal to slight) were also observed in some animals receiving DepoFoam alone (DepoCyte vesicles without cytarabine) but not in sodium chloride solution control animals. Mouse, rat and dog studies have shown that free cytarabine is highly toxic for the haemopoietic system.
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with DepoCyte. The active ingredient, cytarabine, was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and sister chromatid exchange in human leukocytes) and in vivo (chromosome aberrations and sister chromatid exchange assay in rodent bone marrow, mouse micronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in vitro. Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations occurred in mice given intraperitoneal (i.p.) cytarabine. No studies assessing the impact of cytarabine on fertility are available in the literature. Because the systemic exposure to free cytarabine following intrathecal treatment with DepoCyte was negligible, the risk of impaired fertility is likely to be low.
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