TY - JOUR
T1 - Application of static modeling in the prediction of in vivo drug-drug interactions between rivaroxaban and antiarrhythmic agents based on in vitro inhibition studies
AU - Cheong, Eleanor Jing Yi
AU - Goh, Janice Jia Ni
AU - HONG, Yanjun
AU - Venkatesan, Gopalakrishnan
AU - Liu, Yuanjie
AU - Chiu, Gigi Ngar Chee
AU - Kojodjojo, Pipin
AU - Chan, Eric Chun Yong
N1 - This research was supported by the Singapore Ministry of Education [Tier 1 Academic Research Funding, Grant R-148-000-193-112] and the National University of Singapore Department of Pharmacy [Final Year Project Funding, Grant C-148-000-003-001 (to E.C.Y.C.)].
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014161714&partnerID=8YFLogxK
U2 - 10.1124/dmd.116.073890
DO - 10.1124/dmd.116.073890
M3 - Journal article
C2 - 28053220
AN - SCOPUS:85014161714
SN - 0090-9556
VL - 45
SP - 260
EP - 268
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 3
ER -