Journal of Neuro-Oncology

, Volume 81, Issue 2, pp 201–208 | Cite as

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

  • Surasak PhuphanichEmail author
  • Bernard Maria
  • Rene Braeckman
  • Marc Chamberlain
Clinical Study



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).


Encapsulated cytarabine DepoCyt® Ara-C Cytosine arabinoside Neoplastic meningitis Pharmacokinetics 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



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.


  1. 1.
    Chamberlain M, Kormanik P (1998) Neoplastic meningitis: a guide to diagnosis and treatment. CNS Drugs 10:25–41CrossRefGoogle Scholar
  2. 2.
    Olson ME, Chernik NL, Posner JB (1974) Infiltration of the leptomeninges by systemic cancer A clinical and pathologic study. Arch Neurol 30:122–137PubMedGoogle Scholar
  3. 3.
    Wasserstrom WR, Glass JP, Posner JB (1982) Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 49:759–772PubMedCrossRefGoogle Scholar
  4. 4.
    Patchell RA, Posner JB (1985) Neurologic complications of systemic cancer. Neurol Clin 3:729–750PubMedGoogle Scholar
  5. 5.
    Kesari S, Batchelor TT (2003) Leptomeningeal metastases. Neurol Clin 21:25–66PubMedCrossRefGoogle Scholar
  6. 6.
    Shapiro WR (1975) Chemotherapy of primary malignant brain tumors in children. Cancer 35(3 suppl):965–972PubMedCrossRefGoogle Scholar
  7. 7.
    Zimm S, Collins JM, Miser J, Chatterji D, Poplack DG (1984) Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 35:826–830PubMedCrossRefGoogle Scholar
  8. 8.
    Graham FL, Whitmore GF (1970) The effect of beta- D-arabinofuranosylcytosine on growth, viability, and DNA synthesis of mouse L-cells. Cancer Res 30:2627–2635PubMedGoogle Scholar
  9. 9.
    Kim S, Chatelut E, Kim JC et al (1993) Extended CSF cytarabine exposure following intrathecal administration of DTC 101. J Clin Oncol 11:2186–2193PubMedGoogle Scholar
  10. 10.
    Glantz MJ, LaFollette S, Jaeckle KA et al (1999) Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 17:3110–3116PubMedGoogle Scholar
  11. 11.
    Glantz MJ, Jaeckle KA, Chamberlain MC et al (1999) A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt®) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5:3394–3402PubMedGoogle Scholar
  12. 12.
    Jaeckle KA, Phuphanich S, Bent MJ et al (2001) Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 84:157–163PubMedCrossRefGoogle Scholar
  13. 13.
    Jaeckle KA, Batchelor T, O’Day SJ et al (2002) An open label trial of sustained-release cytarabine (DepoCyt®) for the intrathecal treatment of solid tumor neoplastic meningitis. J Neurooncol 57:231–239PubMedCrossRefGoogle Scholar
  14. 14.
    Chamberlain MC, Kormanik P, Howell SB, Kim S (1995) Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases. Arch Neurol 52:912–917PubMedGoogle Scholar
  15. 15.
    Blaney SM, Balis FM, Poplack DG (1991) Pharmacologic approaches to the treatment of meningeal malignancy. Oncology (Huntingt) 5:107–116 discussion 123, 127Google Scholar
  16. 16.
    Blaney SM, Balis FM, Poplack DG (1991) Current pharmacological treatment approaches to central nervous system leukaemia. Drugs 41:702–716PubMedGoogle Scholar
  17. 17.
    Chamberlain MC, Khatibi S, Kim JC, Howell SB, Chatelut E, Kim S (1993) Treatment of leptomeningeal metastasis with intraventricular administration of depot cytarabine (DTC 101) A phase I study. Arch Neurol 50:261–264PubMedGoogle Scholar
  18. 18.
    Momparler RL, Onetto-Pothier N, Bouffard DY, Momparler LF (1990) Cellular pharmacology of 1-beta-D-arabinofuranosylcytosine in human myeloid, B-lymphoid and T-lymphoid leukemic cells. Cancer Chemother Pharmacol 27:141–146PubMedCrossRefGoogle Scholar
  19. 19.
    Raijmakers R, de Witte T, Linssen P, Wessels J, Haanen C (1986) The relation of exposure time and drug concentration in their effect on cloning efficiency after incubation of human bone marrow with cytosine arabinoside. Br J Haematol 62:447–453PubMedGoogle Scholar
  20. 20.
    Muus P, Haanen C, Raijmakers R, de Witte T, Salden M, Wessels J (1987) Influence of dose and duration of exposure on the cytotoxic effect of cytarabine toward human hematopoietic clonogenic cells. Semin Oncol 14(suppl 1):238–244PubMedGoogle Scholar
  21. 21.
    Esteva FJ, Soh LT, Holmes FA, Plunkett W, Meyers CA, Forman AD, Hortobagyi GN (2000) Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 46:382–386PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Surasak Phuphanich
    • 1
    Email author
  • Bernard Maria
    • 2
  • Rene Braeckman
    • 3
  • Marc Chamberlain
    • 4
  1. 1.Neuro-Oncology, Department of Hematology-Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA
  2. 2.Medical University of South CarolinaCharlestonUSA
  3. 3.Valeant Research and DevelopmentCosta MesaUSA
  4. 4.Moffitt Cancer CenterTampaUSA

Personalised recommendations