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

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 (C max ) 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 C max was significantly decreased by ~ 21% in the fed state. Median T max 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 C max and T max 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.

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

“…Oral azacitidine can be taken with or without food [ 35 , 36 ]. At clinically relevant concentrations, oral azacitidine does not substantially inhibit or induce cytochrome P450 enzymes [ 20 ], decreasing the risk of adverse drug interactions, and oral azacitidine pharmacokinetics are not meaningfully altered by coadministration of a PPI [ 36 ].…”

Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

“…at approved doses, but this goal was not met and CC-486 led to considerable toxicity at higher doses [11]. Later attempts to administer a variety of dosing regimens was successful and revealed that CC-486 is active in patients with myeloid neoplasms [11,13,20,21]. However, in the alternative dosing regimens, effects on DNA methylation were very different to those with standard AZA i.v./s.c.…”

Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies

“…21 Three subsequent trials (AZA PH US 2008 CL008 [NCT00761722], AZA-MDS-004 [NCT01519011], and CC-486-CAGEN-001 [NCT02223052]) evaluated the PK of different Oral-AZA formulations, and the effects of administration with food and modulation of gastric pH with a proton-pump inhibitor (omeprazole) on Oral-AZA PK parameters. 50,51 Administration with food did not meaningfully affect the bioavailability of Oral-AZA or other PK parameters, and coadministration with omeprazole did not require dose adjustment. 50,51…”

“…50,51 Administration with food did not meaningfully affect the bioavailability of Oral-AZA or other PK parameters, and coadministration with omeprazole did not require dose adjustment. 50,51…”