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Research ArticleArticle

Application of static modeling in the prediction of in vivo drug-drug interactions between rivaroxaban and anti-arrhythmic agents based on in vitro inhibition studies

Eleanor Jing Yi Cheong, Janice Jia Ni Goh, Yanjun Hong, Gopalakrishnan Venkatesan, Yuanjie Liu, Gigi Ngar Chee Chiu, Pipin Kojodjojo and Eric Chun Yong Chan
Drug Metabolism and Disposition January 4, 2017, dmd.116.073890; DOI: https://doi.org/10.1124/dmd.116.073890
Eleanor Jing Yi Cheong
National University of Singapore;
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Janice Jia Ni Goh
National University of Singapore;
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Yanjun Hong
National University of Singapore;
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Gopalakrishnan Venkatesan
National University of Singapore;
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Yuanjie Liu
National University of Singapore;
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Gigi Ngar Chee Chiu
National University of Singapore;
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Pipin Kojodjojo
National University Heart Centre
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Eric Chun Yong Chan
National University of Singapore;
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  • ORCID record for Eric Chun Yong Chan
  • For correspondence: phaccye@nus.edu.sg
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Abstract

Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in non-valvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism and P-gp efflux pathways. Amiodarone and dronedarone are anti-arrhythmic agents employed in AF management. Amiodarone, dronedarone and their major metabolites, N-desethylamiodarone (NDEA) and N-desbutyldronedarone (NDBD) demonstrate inhibitory effects on CYP3A4 and CYP2J2 with FDA recommended probe substrates. Additionally, both amiodarone and dronedarone are known P-gp inhibitors. Hence, the concomitant administration of these anti-arrhythmic agents has the potential to augment the systemic exposure of rivaroxaban through simultaneous impairment of its clearance pathways. Currently, however, there is a lack of clinical data on the extent of these postulated DDIs. In this study, in vitro inhibition assays using rivaroxaban as the probe substrate demonstrated that both dronedarone and NDBD produced reversible inhibition as well as irreversible mechanism-based inactivation (MBI) of CYP3A4- and CYP2J2-mediated metabolism of rivaroxaban. However, amiodarone and NDEA were observed to cause reversible inhibition as well as MBI of CYP3A4 but not CYP2J2. Additionally, amiodarone, NDEA and dronedarone but not NDBD were determined to inhibit P-gp mediated rivaroxaban transport. The in vitro inhibition parameters were fitted into a mechanistic static model which predicted a 37% and 31% increase in rivaroxaban exposure due to the inhibition of hepatic and gut metabolism by amiodarone and dronedarone respectively. A separate model quantifying the inhibition of P-gp mediated efflux by amiodarone or dronedarone projected a 9% increase in rivaroxaban exposure.

  • cytochrome P450
  • drug-drug interactions
  • efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
  • enzyme inactivation/mechanism-based inhibition
  • enzyme inhibitors
  • in vitro-in vivo prediction (IVIVE)
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 46 (5)
Drug Metabolism and Disposition
Vol. 46, Issue 5
1 May 2018
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Research ArticleArticle

Application of static modeling in the prediction of in vivo drug-drug interactions between rivaroxaban and anti-arrhythmic agents based on in vitro inhibition studies

Eleanor Jing Yi Cheong, Janice Jia Ni Goh, Yanjun Hong, Gopalakrishnan Venkatesan, Yuanjie Liu, Gigi Ngar Chee Chiu, Pipin Kojodjojo and Eric Chun Yong Chan
Drug Metabolism and Disposition January 4, 2017, dmd.116.073890; DOI: https://doi.org/10.1124/dmd.116.073890

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Research ArticleArticle

Application of static modeling in the prediction of in vivo drug-drug interactions between rivaroxaban and anti-arrhythmic agents based on in vitro inhibition studies

Eleanor Jing Yi Cheong, Janice Jia Ni Goh, Yanjun Hong, Gopalakrishnan Venkatesan, Yuanjie Liu, Gigi Ngar Chee Chiu, Pipin Kojodjojo and Eric Chun Yong Chan
Drug Metabolism and Disposition January 4, 2017, dmd.116.073890; DOI: https://doi.org/10.1124/dmd.116.073890
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