In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

摘要

Abstract Several protein kinase inhibitors have been reported to affect cytochrome P450 ( CYP ) 3A by time‐dependent inhibition. Herein, we tested a set of six kinase inhibitors for time‐dependent inhibition of CYP 2C8 and CYP 3A4 in human liver microsomes. Dovitinib, midostaurin and nintedanib exhibited an increased inhibition of CYP 3A4 after a 30‐min. pre‐incubation with NADPH , as compared to no pre‐incubation ( IC 50 shift 1.5). Masitinib, trametinib and vatalanib did not affect CYP 2C8 or CYP 3A4 by time‐dependent inhibition ( IC 50 shift 1.5). The inhibitory mechanism of CYP 3A4 by midostaurin and nintedanib, but not by dovitinib, was consistent with irreversible mechanism‐based inhibition. The maximal inactivation rate ( k inact ) and inhibitor concentration that supports half‐maximal rate of inactivation ( K I ) values of midostaurin and nintedanib were 0.052 1/min. and 2.72 μM, and 0.025 1/min. and 17.3 μM, respectively. According to static predictions, inactivation of CYP 3A4 by nintedanib was unlikely to cause drug–drug interactions with clinically used doses of nintedanib, whereas midostaurin was predicted to increase the plasma exposure to CYP 3A4‐dependent substrates several fold. Furthermore, based on reversible inhibition, masitinib and vatalanib were predicted to increase the plasma exposure to sensitive CYP 2C8 and CYP 3A4 substrates by ≥2‐fold. In summary, our data identify midostaurin and nintedanib as time‐dependent inhibitors of CYP 3A4 and detect a risk of drug–drug interactions between vatalanib and CYP 2C8 substrates, and between masitinib, midostaurin and vatalanib and CYP 3A4 substrates. The liability of kinase inhibitors to affect CYP enzymes by time‐dependent inhibition may have long‐term consequences, in terms of drug–drug interactions and toxicities.