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

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/m(2)/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/m(2)/d;, the mean +/- SD Cmax and AUC(0-infinity) at 10 mg/m(2)/d were 776 +/- 459 nM and 1,355 +/- 1,125 h*nM, respectively, and at 75 mg/m(2)/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. (c) 2005 by American Society of Clinical Oncology.