Originally published as JCO Early Release 10.1200/JCO.2005.07.450 on April 25 2005

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Pharmacokinetics of 5-Azacitidine Administered With Phenylbutyrate in Patients With Refractory Solid Tumors or Hematologic Malignancies

Michelle A. Rudek, Ming Zhao, Ping He, Carol Hartke, Jill Gilbert, Steven D. Gore, Michael A. Carducci, Sharyn D. Baker

From the Divisions of Medical Oncology, Experimental Therapeutics, and Hematologic Malignancy, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

Address reprint requests to Michelle A. Rudek, PharmD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, 1650 Orleans St, Room 1M90, Baltimore, MD 21231; e-mail: mrudek2{at}jhmi.edu.

PURPOSE: To characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor.

PATIENTS AND METHODS: Pharmacokinetic data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5-AC at doses ranging from 10 to 75 mg/m²/d was administered once daily as a subcutaneous injection for 5 to 21 days in combination with phenylbutyrate administered as a continuous intravenous infusion for varying dose and duration every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5-AC administration. 5-AC was quantitated using a validated liquid chromatograph/tandem mass spectrometry method.

RESULTS: 5-AC was rapidly absorbed with the mean T_max occurring at 0.47 hour. Average maximum concentration (C_max) and area under the curve (AUC_0-) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m²/d; the mean ± SD C_max and AUC_0- at 10 mg/m²/d were 776 ± 459 nM and 1,355 ± 1,125 h*nM, respectively, and at 75 mg/m²/d were 4,871 ± 1,398 nM and 6,582 ± 2,560 h*nM, respectively. Despite a short terminal half-life of 1.5 ± 2.3 hours, inhibition of DNA methyl transferase activity in tumors of patients receiving 5-AC has been documented.

CONCLUSION: 5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.

Supported by National Institutes of Health grants P30CA069773, U01CA70095, R01CA75525, and R01CA87760. Steven D. Gore was the recipient of a Scholar Award in Clinical Research from the Leukemia and Lymphoma Society of America.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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