In Vitro Measurement and In Vivo Prediction of Combination Safety of
Rivaroxaban with Tyrosine Kinase Inhibitors: A Medication Safety
Assessment Study
Abstract
Background and Purpose: Rivaroxaban as an oral anticoagulant is widely
used for the prevention and treatment of thromboembolic disease.
Previous studies revealed cytochrome P450 (CYP)–mediated metabolism of
rivaroxaban mainly involves CYP2J2 and CYP3A4. Imatinib, sunitinib and
gefitinib are three tyrosine kinase inhibitors (TKIs) that are
extensively applied for anti-cancer therapy. Statistical research has
shown cancer patients are at approximately 4-7–fold higher risk of vein
thromboembolism than normal patients. Therefore, rivaroxaban and TKIs
have a profound combination foundation. This study aimed to
comprehensively assess the combination safety of rivaroxaban with TKIs
in vitro. Experimental Approach: First, the inhibitory activity of the
three TKIs was screened. Second, to comprehensively evaluate their
inhibitory potential, the reversible and mechanism-dependent inhibitory
kinetic constants of three TKIs on CYP2J2 and CYP3A4 were determined.
Docking simulation was used to explore the molecular mechanism. Finally,
drug-drug interaction (DDI) risks of the combination were assessed using
pharmacokinetic data of cancer patients. Key Results: Imatinib and
gefitinib exerted significant reversible inhibition of both CYP2J2 and
CYP3A4, while sunitinib only showed reversible inhibition of CYP3A4, not
CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4 and
slightly on CYP2J2. Notably, sunitinib had a significantly stronger
inactivation effect on CYP3A4 than the other TKIs, with a 4.14-fold IC50
shift. Imatinib was predicted to cause a 114–244% increase in
rivaroxaban exposure. Conclusion and Implication: Imatinib showed the
strongest inhibition, which was predicted to have a moderate DDI risk.
These results provide evidence for medication guidance when combining
rivaroxaban with TKIs.