Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

Hani M. Babiker, Mohammed Milhem, Joseph Aisner, William Edenfield, Dale Shepard, Michael Savona, Swaminathan Padmanabhan Iyer, Maen Abdelrahim, C. L. Beach, Barry Skikne, Eric Laille, Kao Tai Tsai, Thai Ho

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Abstract

Purpose: CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A). Methods: We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study. Results: The ratios of the geometric means of the maximum azacitidine plasma concentration (Cmax) and of the area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of Cmax was significantly decreased by ~ 21% in the fed state. Median Tmax was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P < 0.001). Nevertheless, systemic drug exposure (AUC) in fed and fasted states was within the 80–125% boundaries of bioequivalence and differences in Cmax and Tmax are not expected to have a clinical impact. Conclusion: The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.

Original languageEnglish (US)
Pages (from-to)621-626
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume85
Issue number3
DOIs
StatePublished - Feb 8 2020

Keywords

  • Bioequivalence
  • CC-486
  • Oral azacitidine
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Babiker, H. M., Milhem, M., Aisner, J., Edenfield, W., Shepard, D., Savona, M., Iyer, S. P., Abdelrahim, M., Beach, C. L., Skikne, B., Laille, E., Tsai, K. T., & Ho, T. (2020). Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer. Cancer Chemotherapy and Pharmacology, 85(3), 621-626. https://doi.org/10.1007/s00280-020-04037-9