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

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 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 (IC shift >1.5). Masitinib, trametinib and vatalanib did not affect CYP2C8 or CYP3A4 by time-dependent inhibition (IC 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 (k ) and inhibitor concentration that supports half-maximal rate of inactivation (K ) 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.

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Indeed, most of the TKI shown to induce RM in the first part of this review have been reported to cause CYP3A4 TDI, some of them also exhibiting a weak or moderate CYP2C8 TDI . The second part of the review thus summarizes the results of studies on CYP inactivation by TKI, especially when it is supported by evidence of RM formation in the presence of trapping agents.…”

“…Several studies have demonstrated that most TKI are prone to causing DDI since they are oral drugs prescribed over a long period of time to patients with comedications and because they are CYP inhibitors. TKI interfere with CYP by direct or reversible inhibition, but also by MBI . MBI arises from the bioactivation of drugs to RM, that have the propensity to permanently inactivate the enzyme involved in their generation by different mechanisms covalent binding to the heme porphyrin ring; co‐ordination (quasi‐irreversible binding) to the prosthetic heme iron to form a metabolite‐intermediate (MI) complex; covalent binding to the apoprotein, especially to key amino acids with nucleophilic side chains (arginine, cysteine, and lysine).…”

“…Filppula et al screened lestaurtinib 103 and nintedanib 104 (Figure ) for CYP2C8 and CYP3A MBI. No CYP2C8 TDI was evidenced, whereas irreversible CYP3A4 TDI was observed for both drugs.…”

“…RM have the propensity to covalently bind to proteins and DNA causing cellular damage and cell death. RM can also interact with cytochromes P450 (CYP) and be responsible for their time‐dependent inhibition (TDI), also called mechanism‐based inhibition (MBI) or inactivation, leading to pharmacokinetic drug‐drug interactions (DDI) …”

New Food and Drug Administration–Approved and Emerging Novel Treatment Options for Acute Myeloid Leukemia

“…Midostaurin is primarily metabolized by cytochrome P450 (CYP) 3A4 to two active metabolites: CGP62221 and CGP52421 . It exhibits time‐dependent pharmacokinetics and autoinduction, allowing peak concentrations during the first week of therapy, then decreasing to steady state by day 28 . Due to its metabolism, drug–drug interactions (DDI) are of concern.…”