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Model-Based Risk Prediction of Rivaroxaban with Amiodarone for Moderate Renal Impaired Elderly Population

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Abstract

Purpose

Increased bleeding risk was found associated with concurrent prescription of rivaroxaban and amiodarone. We previously recommended dose adjustment for rivaroxaban utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Our subsequent in vitro studies discovered the pivotal involvement of human renal organic anion transporter 3 (hOAT3) in the renal secretion of rivaroxaban and the inhibitory potency of amiodarone. This study aimed to redefine the disease-drug-drug interactions (DDDI) between rivaroxaban and amiodarone and update the potential risks.

Methods

Prospective simulations were conducted with updated PBPK models of rivaroxaban and amiodarone incorporating hOAT3-related parameters.

Results

Simulations to recapitulate previously explored DDDI in renal impairment showed a higher bleeding tendency in all simulation scenarios after integrating hOAT3-mediated clearance into PBPK models. Further sensitivity analysis revealed that both hOAT3 dysfunction and age could affect the extent of DDDI, and age was shown to have a more pivotal role on rivaroxaban in vivo exposure. When amiodarone was prescribed along with our recommended dose reduction of rivaroxaban to 10 mg in moderate renal impaired elderly people, it could result in persistently higher rivaroxaban peak concentrations at a steady state. To better manage the increased bleeding risk among such a vulnerable population, a dose reduction of rivaroxaban to 2.5 mg twice daily resulted in its acceptable in vivo exposure.

Conclusion

Close monitoring of bleeding tendency is essential for elderly patients with moderate renal impairment receiving co-prescribed rivaroxaban and amiodarone. Further dose reduction is recommended for rivaroxaban to mitigate this specific DDDI risk.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

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Funding

This study was funded by the National University Heart Centre Singapore (NUHCS) Cardiovascular Research Institute (CVRI)—Core Fund (Grant Number NUHSRO/2019/082/Core) and SCEPTRE CG Seed Grant (Grant Number NMRC/CG/M008/2017).

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Ziteng Wang, Eleanor Jing Yi Cheong & Eric Chun Yong Chan

  2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Pipin Kojodjojo

Authors
  1. Ziteng Wang
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  2. Eleanor Jing Yi Cheong
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  3. Pipin Kojodjojo
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  4. Eric Chun Yong Chan
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Contributions

Ziteng Wang, Eleanor Jing Yi Cheong and Eric Chun Yong Chan designed the study; Ziteng Wang and Eleanor Jing Yi Cheong performed simulations; Pipin Kojodjojo provided clinical advice; Ziteng Wang, Eleanor Jing Yi Cheong and Eric Chun Yong Chan wrote the manuscript; Ziteng Wang, Pipin Kojodjojo and Eric Chun Yong Chan reviewed and/or revised the manuscript.

Corresponding author

Correspondence to Eric Chun Yong Chan.

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The authors declare no competing interests.

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Wang, Z., Cheong, E.J.Y., Kojodjojo, P. et al. Model-Based Risk Prediction of Rivaroxaban with Amiodarone for Moderate Renal Impaired Elderly Population. Cardiovasc Drugs Ther 37, 605–609 (2023). https://doi.org/10.1007/s10557-021-07266-z

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  • DOI: https://doi.org/10.1007/s10557-021-07266-z

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