title: Application of Static Modeling --in the Prediction of In Vivo Drug-Drug Interactions between Rivaroxaban and Antiarrhythmic Agents Based on In Vitro Inhibition Studies.
abstract: Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in nonvalvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism, and P-glycoprotein (P-gp) efflux pathways. Amiodarone and dronedarone are antiarrhythmic 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 U.S. Food and Drug Administration-recommended probe substrates. In addition, both amiodarone and dronedarone are known P-gp inhibitors. Hence, the concomitant administration of these antiarrhythmic agents has the potential to augment the systemic exposure of rivaroxaban through simultaneous impairment of its clearance pathways. Currently, however, clinical data on the extent of these postulated drug-drug interactions are lacking. 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 of CYP3A4- and CYP2J2-mediated metabolism of rivaroxaban. However, amiodarone and NDEA were observed to cause reversible inhibition as well as mechanism-based inactivation of CYP3A4 but not CYP2J2. In addition, 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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Eleanor Jing Yi
authors.initials: EJ
authors.lastname: Cheong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Janice Jia Ni
authors.initials: JJ
authors.lastname: Goh
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Venkatesan
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Gigi Ngar Chee
authors.initials: GN
authors.lastname: Chiu
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.).
authors.forename: Pipin
authors.initials: P
authors.lastname: Kojodjojo
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore (E.J.Y.C., J.J.N.G., Y.H., G.V., Y.L., G.N.C.C., E.C.Y.C.); Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Ho Sin Hang Campus, Hong Kong (Y.H.); Department of Cardiology and Cardiac Electrophysiology, National University Heart Centre, Singapore (P.K.); and Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore (E.C.Y.C.) phaccye@nus.edu.sg.
authors.forename: Eric Chun Yong
authors.initials: EC
authors.lastname: Chan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D011994:Recombinant Proteins; D000069552:Rivaroxaban / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D000069552:Rivaroxaban; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A