Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban

Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently FDA-approved for the treatment of advanced or metastatic cholangiocarcinoma. We previously established that INF inhibited and inactivated cytochrome P450 3A4 (CYP3A4). Here, in a follow-up to our previous study, we identified for the first time that INF also elicited potent competitive inhibition and mechanism-based inactivation (MBI) of CYP2J2 with kinetic parameters K i, K I, k inact, and partition ratio of 1.94 µM, 0.10 µM, 0.026 min-1 and ~3 respectively when rivaroxaban was harnessed as the probe substrate. Inactivation was revealed to exhibit cofactor-dependency and was attenuated by an alternative substrate (astemizole) and direct inhibitor (nilotinib) of CYP2J2. Additionally, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from covalent modification due to the lack of substantial enzyme activity recovery following dialysis and chemical oxidation as well as the lack of a resolvable Soret band in spectral scans. Glutathione trapping confirmed that the identity of the putative reactive intermediate implicated in the covalent inactivation of both CYP2J2 and CYP3A4 was identical and likely attributable to an electrophilic p-benzoquinonediimine intermediate of INF. Finally, mechanistic static modelling revealed that by integrating the previously arcane inhibition and inactivation kinetic parameters of CYP2J2-mediated rivaroxaban hydroxylation by INF illuminated in this work together with those previously documented for CYP3A4, a 49% increase in the systemic exposure of rivaroxaban was projected. Our modelling results predicted a potential risk of metabolic DDI between the clinically-relevant combination of rivaroxaban and INF in the setting of cancer. Significance Statement In this study, we reported that INF elicits potent reversible inhibition and MBI of CYP2J2. Furthermore, static modelling predicted that its coadministration with the direct oral anticoagulant rivaroxaban may potentially culminate in an metabolic DDI leading to an increased risk of major bleeding. As rivaroxaban is steadily gaining prominence as the anticoagulant of choice in the treatment of cancer-associated venous thromboembolism, the DDI projections reported here are clinically-relevant and warrants further investigation via physiologically-based pharmacokinetic modelling and simulation.

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