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

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 CYP2C8 and CYP3A4 in human liver microsomes. Dovitinib, midostaurin and nintedanib exhibited an increased inhibition of CYP3A4 after a 30‐min. pre‐incubation with NADPH, as compared to no pre‐incubation (IC50 shift >1.5). Masitinib, trametinib and vatalanib did not affect CYP2C8 or CYP3A4 by time‐dependent inhibition (IC50 shift <1.5). The inhibitory mechanism of CYP3A4 by midostaurin and nintedanib, but not by dovitinib, was consistent with irreversible mechanism‐based inhibition. The maximal inactivation rate (kinact) and inhibitor concentration that supports half‐maximal rate of inactivation (KI) 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 CYP3A4 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 CYP3A4‐dependent substrates several fold. Furthermore, based on reversible inhibition, masitinib and vatalanib were predicted to increase the plasma exposure to sensitive CYP2C8 and CYP3A4 substrates by ≥2‐fold. In summary, our data identify midostaurin and nintedanib as time‐dependent inhibitors of CYP3A4 and detect a risk of drug–drug interactions between vatalanib and CYP2C8 substrates, and between masitinib, midostaurin and vatalanib and CYP3A4 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.