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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.

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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.

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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
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  2. M L Stoltz
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  3. M R Ward
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  4. H Kantarjian
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  5. S Sharma
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Correspondence to G Garcia-Manero.

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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

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