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

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


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 Tmax occurring at 0.47 hour. Average maximum concentration (Cmax) and area under the curve (AUC0-∞) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m2/d; the mean ± SD Cmax and AUC0-∞ 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.

Original languageEnglish (US)
Pages (from-to)3906-3911
Number of pages6
JournalJournal of Clinical Oncology
Issue number17
StatePublished - 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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