Absorption, distribution, metabolism, and excretion of mTOR kinase inhibitor CC-223 in rats, dogs, and humans

Abstract

1. The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [¹⁴C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg), and healthy volunteers (20 mg; 200 nCi).

2. CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans. Urine and bile each contained approximately 20% administered radioactivity in rats, whereas bile (20%) played a more important role than urine (<10%) in the excretion of absorbed radioactivity in dogs. Based on excretion data, CC-223 had good absorption, with greater than 56%, 29%, and 57% of the oral dose absorbed in rats, dogs, and humans, respectively.

3. CC-223 was the prominent radioactive component in circulation of rats (>71% of the exposure to total radioactivity) and dogs (≥45.5%), whereas M1 (76.5%) was the predominant circulating metabolite in humans. M1 and M1-derived metabolites accounted for >66% of human dose. CC-223 was extensively metabolized in rats, dogs, and humans through glucuronidation, O-demethylation, oxidation, and combinations of these pathways.

Keywords:

• Accelerator mass spectrometry
• ADME
• mTOR kinase inhibitor
• species comparison

Acknowledgements

The authors would like to thank Gondi Kumar for his guidance with the studies and review of the manuscript, and also thank QPS, LLC, and Covance, Inc. for their contribution to the in-life phase of the studies.

Declaration of interest

This work was funded by Celgene Corporation. All authors are employees for Celgene Corporation.

Supplementary material available online