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A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4
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  • tingting Zhao,
  • Xuening Li,
  • Yanwei Chen,
  • Dalong Wang,
  • Liyan Wang,
  • Shan Zhao,
  • Changyuan Wang,
  • Qiang Meng,
  • Huijun Sun,
  • Kexin Liu,
  • Jingjing Wu
tingting Zhao
Dalian Medical University
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Xuening Li
Dalian Medical University
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Yanwei Chen
First Affiliated Hospital of Dalian Medical University
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Dalong Wang
Dalian Medical University
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Liyan Wang
First Affiliated Hospital of Dalian Medical University
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Shan Zhao
Chinese Academy of Sciences
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Changyuan Wang
Dalian Med Univ
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Qiang Meng
Dalian Medical University
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Huijun Sun
Dalian Medical University
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Kexin Liu
Dalian Medical University
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Jingjing Wu
Dalian Medical University
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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.

Peer review status:UNDER REVIEW

17 Jun 2021Submitted to British Journal of Pharmacology
18 Jun 2021Assigned to Editor
18 Jun 2021Submission Checks Completed
30 Jun 2021Reviewer(s) Assigned
19 Sep 2021Review(s) Completed, Editorial Evaluation Pending