Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Therapy

A pilot pharmacokinetic study of oral azacitidine

Leukemia volume 22, pages 1680–1684 (2008)Cite this article

Abstract

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m2 for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Herman JG, Baylin SB . Gene silencing in cancer in association with promoter hypermethylation. N Eng J Med 2003; 349: 2042–2054.

    Article  CAS  Google Scholar 

  2. Jones PA, Taylor SM, Wilson VL . Inhibition of DNA methylation by 5-azacytidine. Recent Results Cancer Res 1983; 84: 202–211.

    CAS  PubMed  Google Scholar 

  3. Santi DV, Garrett CE, Barr PJ . On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell 1983; 33: 9–10.

    Article  CAS  PubMed  Google Scholar 

  4. Gabbara S, Bhagwat AS . The mechanism of inhibition of DNA (cytosine-5-)-methyltransferases by 5-azacytosine is likely to involve methyl transfer to the inhibitor. Biochem J 1995; 307: 87–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bird AP . The relationship of DNA methylation to cancer. Cancer Surv 1996; 28: 87–101.

    CAS  PubMed  Google Scholar 

  6. Jones PA, Laird PW . Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.

    Article  CAS  PubMed  Google Scholar 

  7. Karpf AR, Jones DA . Reactivating the expression of methylation silenced genes in human cancer. Oncogene 2002; 21: 5496–5503.

    Article  CAS  PubMed  Google Scholar 

  8. Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 1997; 90: 1403–1409.

    CAS  PubMed  Google Scholar 

  9. Herman JG, Jen J, Merlo A, Baylin SB . Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 1996; 56: 722–727.

    CAS  PubMed  Google Scholar 

  10. Li LH, Olin EJ, Buskirk HH, Reineke LM . Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 1970; 30: 2760–2769.

    CAS  Google Scholar 

  11. Li LH, Olin EJ, Fraser TJ, Bhuyan BK . Phase specificity of 5-azacytidine against mammalian cells in tissue culture. Cancer Res 1970; 30: 2770–2775.

    CAS  PubMed  Google Scholar 

  12. Silverman LR . Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist 2001; 6: 8–14.

    Article  CAS  PubMed  Google Scholar 

  13. Jones PA, Taylor SM, Wilson V . DNA modification, differentiation, and transformation. J Exp Zool 1983; 228: 287–295.

    Article  CAS  PubMed  Google Scholar 

  14. Leone G, Teofili L, Voso MT, Lübbert M . DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica 2002; 87: 1324–1341.

    CAS  PubMed  Google Scholar 

  15. Silverman LR, Holland JF, Demakos EP, Peterson B, Nelson DA, Clamon G et al. Azacitidine (Aza C) in myelodysplastic syndromes (MDS), CALGB studies 8421 and 8921. Ann Hematol 1994; 68: A12, (abstract 46).

    Google Scholar 

  16. Chabner BA, Drake JC, Johns DG . Deamination of 5-azacitidine by a human leukemia cell cytidine deaminase. Biochem Pharmacol 1973; 22: 2763–2765.

    Article  CAS  PubMed  Google Scholar 

  17. Robertson KD, Jones PA . DNA methylation: past, present and future directions. Carcinogenesis 2000; 21: 461–467.

    Article  CAS  PubMed  Google Scholar 

  18. Pharmion Corporation. Azacitidine Investigator's Brochure, 5th edn. Boulder, CO, 2007.

  19. Marcucci G, Silverman L, Eller M, Lintz L, Beach CL . Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 2005; 45: 597–602.

    Article  CAS  PubMed  Google Scholar 

  20. Silverman L, McKenzie D, Peterson B, Demakos E, Malone N, Holland J et al. Azacitidine prolongs survival and time to AML transformation in high-risk myeloblastic syndrome (MDS) patients ⩾65 years of age. Blood 2005; 106: 790a, (abstract 2524).

    Article  Google Scholar 

  21. Silverman LA, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429–2440.

    Article  CAS  Google Scholar 

  22. Fenaux P, Mufti GJ, Finelli C, Giagounidis A, Schroch R, List AF et al. Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional car regimens (CCR): results of the AZA-001 phase III study. American Society of Hematology Annual Meeting Proceedings. Blood 2007; 110: 250a (abstract: 817).

  23. Soriano A, Braiteh F, Garcia-Manero G, Camacho L, Hong D, Moulder S et al. Combination of 5-azacytidine (5-AZA) and valproic acid (VPA) in advanced solid cancers: A phase I study. J Clin Oncol 2007; 25: 149s (abstract: 3547).

  24. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F et al. Safety and clinical activity of the combination of 5-azcytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007; 110: 2302–2308.

    Article  CAS  Google Scholar 

  25. Gore S, Jiemjit A, Silverman L, Aucott T, Baylin S, Carraway H et al. Combined methyltransferase/histone deacetylase inhibition with 5-azacitidine and MS-275 in patients with MDS, CMMoL, and AML: clinical response, histone acetylation and DNA damage. American Society of Hematology Annual Meeting Proceedings. Blood 2006; 108: 1569, (abstract 517).

    Article  Google Scholar 

  26. Dunbar C, Travis W, Kan YW, Nienhuis A . 5-Azacytidine treatment in a beta (0)-thalassaemic patient unable to be transfused due to multiple alloantibodies. Br J Haematol 1989; 72: 467–468.

    Article  CAS  PubMed  Google Scholar 

  27. Dover GJ, Charache S, Boyer SH, Vogelsang G, Moyer M . 5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: dose-response analysis of subcutaneous and oral dosage regimens. Blood 1985; 66: 527–532.

    CAS  PubMed  Google Scholar 

  28. Dover GJ, Charache S, Nora R, Boyer SH . Progress toward increasing fetal hemoglobin production in man: experience with 5-azacytidine and hydroxyurea. Ann N Y Acad Sci 1985; 445: 218–224.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge Jovanka Solorzano (MBA), Clinical Operations, Pharmion Corporation; Eric Laille (MS) and Azmi Nasser (B.Pharm, PhD), Department of Clinical Pharmacology, Pharmion Corporation and Margaret Beatty (DVM, MS), Medical and Science Writing for their assistance with data analyses and manuscript preparation. This study was supported by Pharmion Corporation. GG-M is supported in part by a Physician-Scientist Award funded by the Commonwealth Cancer Foundation for Research and a Leukemia and Lymphoma Translational Research Grant #6173-07 and also supported in part by NCI Grant 5P01 CA108631.

Author information

Authors and Affiliations

  1. Department of Leukemia, University of Texas M D Anderson Cancer, Houston, TX, USA

    G Garcia-Manero & H Kantarjian

  2. Pharmion Corporation, Overland Park, KS and San Francisco, CA, USA

    M L Stoltz & M R Ward

  3. The Nevada Cancer Institute, Las Vegas, NV, USA

    S Sharma

Authors
  1. G Garcia-Manero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M L Stoltz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M R Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Kantarjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Garcia-Manero.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garcia-Manero, G., Stoltz, M., Ward, M. et al. A pilot pharmacokinetic study of oral azacitidine. Leukemia 22, 1680–1684 (2008). https://doi.org/10.1038/leu.2008.145

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.145

Keywords

This article is cited by

Search

Advanced search

Quick links