Assessment of drug-drug interactions of CC-90001, a potent and selective inhibitor of c-Jun N-terminal kinase
CC-90001 is primarily metabolized through glucuronidation, with oxidative metabolism serving as a minor pathway in human hepatocytes and liver microsomes. In vitro, the glucuronidation of CC-90001 is catalyzed by UGT1A9, UGT1A4, and UGT1A1, while oxidative metabolism is predominantly mediated by CYP3A4/5, with minor contributions from CYP1A2, CYP2C9, CYP2B6, and CYP2D6. At a concentration of 100 μM, CC-90001 inhibits CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 by up to 55%, with negligible inhibition observed at concentrations ≤30 μM. Additionally, CC-90001 is not a time-dependent inhibitor of CYP enzymes.
In human hepatocytes, CC-90001 induces the expression of CYP2B6 and CYP3A, with mRNA levels increasing by 34.4% to 52.8% relative to positive controls. In vitro, CC-90001 acts as both a substrate and inhibitor of several transporters, including P-gp, BCRP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2k, with IC50 values of 30.3, 25.8, 17.7, 0.417, 19.9, 0.605, 4.17, and 20 μM, respectively. A clinical study indicated that CC-90001 has minimal or no effect on the exposure of warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A), or metformin (OCT2, MATE1/2k). However, co-administration of CC-90001 with other drugs increases their AUCt and Cmax, including a 176% and 339% increase for rosuvastatin (BCRP/OATP1B1/3), a 116% and 171% increase for digoxin (P-gp), and a 266% and 321% increase for nintedanib (CYP3A & P-gp).
In conclusion, CC-90001 is unlikely to cause clinically significant interactions involving CYP enzymes or UGTs. However, weak to moderate interactions may occur with substrates of P-gp and OATP1B1 due to its inhibition of these transporters.