Assessment of drug–drug interaction potential and PBPK modeling of CC-223, a potent inhibitor of the mammalian target of rapamycin kinase

Abstract

1. CC-223 was studied in vitro for metabolism and drug–drug interactions (DDI), and in clinic for interaction with ketoconazole.

2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3) and imine (M13), with M1 being the most prominent metabolite.

3. CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60–70% in healthy volunteers.

4. CC-223 (IC₅₀ ≥ 27 µM) and M1 (IC₅₀ ≥ 46 µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes. CC-223 and M1 were moderate inducers of CYP3A in human hepatocytes.

5. CC-223 was a substrate of BCRP, and M1 was a substrate of P-gp and BCRP. CC-223 was an inhibitor of P-gp (IC₅₀ = 3.67 µM) and BCRP (IC₅₀ = 11.7 µM), but at a clinically relevant concentration showed no inhibition of other transporters examined. M1 is a weak inhibitor of P-gp and BCRP.

6. PBPK model of CC-223 and M1 was developed and verified using clinical results. Model based predictions of DDI with ketoconazole were in agreement with observed results enabling prospective predictions of DDIs between CC-223 and CYP3A4 inhibitors.

Keywords:

• Cytochrome P-450
• drug–drug interactions
• in vitro metabolism
• mTOR kinase inhibitor
• PBPK
• transporters

Acknowledgements

The authors would like to thank Gondi Kumar for his guidance to the studies and review of the manuscript.

Declaration of interest

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