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

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.