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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
Author(s) -
Laille Eric,
Savona Michael R.,
Scott Bart L.,
Boyd Thomas E.,
Dong Qian,
Skikne Barry
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.251
Subject(s) - azacitidine , pharmacokinetics , omeprazole , dosing , medicine , oral administration , pharmacology , capsule , area under the curve , proton pump inhibitor , gastroenterology , chemistry , biochemistry , gene expression , botany , biology , dna methylation , gene
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 (T max ) than the enteric‐coated tablet. Study 2 evaluated only IRT formulations of oral azacitidine. Under fed condition, T max was delayed ∼1.5 hours but area under the concentration–time curve (AUC ∞ ) and maximum plasma concentrations (C max ) were comparable under fed and fasted conditions. Mean azacitidine AUC ∞ and C max 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 C max (%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.