title: Pharmacokinetics of different formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies.
abstract: Parenteral azacitidine improves overall survival in higher-risk myelodysplastic syndromes. An oral azacitidine formulation would allow extended dosing schedules, potentially improving safety and/or efficacy. Two Phase 1 studies evaluated the pharmacokinetics (PK) of oral azacitidine in subjects with hematologic malignancies. Study 1 evaluated different oral formulations (immediate release tablet [IRT], enteric-coated tablet, and capsule; N = 16). Study 2 assessed the effect of food (Part 1; N = 17) and gastric pH modulation with omeprazole (Part 2; N = 14) on oral azacitidine PK. Azacitidine plasma concentration-time profiles for IRT and capsule formulations were similar, with more rapid time to maximum plasma concentration (Tmax ) than the enteric-coated tablet. Study 2 evaluated only IRT formulations of oral azacitidine. Under fed condition, Tmax was delayed ∼1.5 hours but area under the concentration-time curve (AUC∞ ) and maximum plasma concentrations (Cmax ) were comparable under fed and fasted conditions. Mean azacitidine AUC∞ and Cmax increased upon omeprazole co-administration (18.3% and 13.2%, respectively, vs. oral azacitidine alone), but not to a clinically meaningful extent. High inter-subject variability in AUC∞ and Cmax (%CV range 46.4-68.9%) was observed. Oral azacitidine is rapidly absorbed with little or no effect of food on PK parameters, and does not require dose adjustments when taking a proton-pump inhibitor.
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Laille
authors.forename: Michael R
authors.initials: MR
authors.lastname: Savona
authors.forename: Bart L
authors.initials: BL
authors.lastname: Scott
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Boyd
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.forename: Barry
authors.initials: B
authors.lastname: Skikne
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001374:Azacitidine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D005260:Female; D018565:Food-Drug Interactions; D019337:Hematologic Neoplasms / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D013270:Stomach / Q000737:chemistry; D013607:Tablets
chemical_list: D000964:Antimetabolites, Antineoplastic; D002214:Capsules; D003692:Delayed-Action Preparations; D013607:Tablets; D001374:Azacitidine
keywords: CC-486; effect of food; formulation; oral azacitidine; pharmacokinetics; proton-pump inhibitor