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Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies.

Author(s): Rudek MA, Zhao M, He P, Hartke C, Gilbert J, Gore SD, Carducci MA, Baker SD

Affiliation(s): Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. mrudek2@jhmi.edu

Publication date & source: 2005-06-10, J Clin Oncol., 23(17):3906-11. Epub 2005 Apr 25.

Publication type: Clinical Trial; Clinical Trial, Phase I; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.

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-infinity)) 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-infinity) 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.

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