Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies.
OBJECTIVE
To characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor.


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.


CONCLUSIONS
5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.
Rudek
Michelle A
MA
Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. mrudek2@jhmi.edu
Zhao
Ming
M
He
Ping
P
Hartke
Carol
C
Gilbert
Jill
J
Gore
Steven D
SD
Carducci
Michael A
MA
Baker
Sharyn D
SD
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001374:Azacitidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000964:Antimetabolites, Antineoplastic; D010654:Phenylbutyrates; D001374:Azacitidine