A pilot pharmacokinetic study of oral azacitidine

• Published in: Leukemia Vol. 22; no. 9; pp. 1680 - 1684
• Main Authors: Garcia-Manero, G, Stoltz, M L, Ward, M R, Kantarjian, H, Sharma, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2008; Nature Publishing; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic agents; Aqueous environments; Azacitidine - administration & dosage; Azacitidine - pharmacokinetics; Bioavailability; Biological and medical sciences; Biological Availability; Cancer Research; Catabolism; Chemotherapy; Clinical trials; Critical Care Medicine; Cytidine deaminase; Dosage; Drug therapy; Drug-Related Side Effects and Adverse Reactions; Feasibility studies; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Intensive; Internal Medicine; Intravenous administration; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Nucleoside analogs; Oncology; original-article; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Pilot Projects; Side effects; Toxicity; Tumors; United States; pharmacokinetics; oral; bioavailability; azacitidine; Antineoplastic agent; Human; Acute myelogenous leukemia; Hematology; Oral administration; Malignant hemopathy; Bioavailability; Myelodysplastic syndrome; Azanucleoside; Chemotherapy; Treatment; Cancerology; Antimetabolic; Azacitidine; Triazine derivatives; Pharmacokinetics; Cancer
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2008.145

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m 2 for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.