A combined medication safety assessment of rivaroxaban with Tyrosine
Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4
Abstract
Background and purpose: Cancer patients are always complicated with vein
thromboembolism, thus the combination of anticoagulants with anti-cancer
drugs has profound foundations. This study aimed to assess the safety of
rivaroxaban comminating with three tyrosine kinase inhibitors (TKIs) in
cancer patients. Experimental Approach: The inhibition of three TKIs on
CYP2J2- and CYP3A4-mediated rivaroxaban metabolism was first screened
and then reversible and mechanism-dependent inhibitory kinetic constants
were determined. Molecular docking was conducted to reveal the
interactions between TKIs and CYP2J2 and CYP3A4. Finally,
pharmacokinetic parameters of cancer patients were used to assess the
safety. Key Results: Imatinib and gefitinib significantly reversibly
inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, while
sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three
TKIs also showed time-dependent inactivation of CYP3A4. Notably,
sunitinib had the strongest inactivation effect on CYP3A4 than the other
TKIs with a 4.00-fold IC50 shift, however, a slight effect on CYP2J2.
Docking simulations revealed the relation of inhibitory activity to
ChemScore. Additionally, drug-drug interaction risks of combinations
were assessed using pharmacokinetic data of cancer patients. Imatinib,
which showed the strongest inhibition, was predicted to cause a
114–244% increase in rivaroxaban exposure. Conclusion and
Implications: Imatinib was predicted to have a moderate DDI risk when
was combined with rivaroxaban. These results provide evidence for
medication guidance when combining rivaroxaban with TKIs for cancer
patients, and also give new insight for the DDI assessment involving
rivaroxaban.