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

Ziteng Wang, Eleanor Jing Yi Cheong, Pipin Kojodjojo, Eric Chun Yong Chan

Cardiovascular drugs and therapy 2023 Jun

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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. Prospective simulations were conducted with updated PBPK models of rivaroxaban and amiodarone incorporating hOAT3-related parameters. 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. 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. © 2021. Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Ziteng Wang, Eleanor Jing Yi Cheong, Pipin Kojodjojo, Eric Chun Yong Chan. Model-Based Risk Prediction of Rivaroxaban with Amiodarone for Moderate Renal Impaired Elderly Population. Cardiovascular drugs and therapy. 2023 Jun;37(3):605-609