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Pharmaceutics. 2019 Mar 19;11(3). pii: E133. doi: 10.3390/pharmaceutics11030133.

Effects of Verapamil and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban.

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College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada.
College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.


Concomitant use of rivaroxaban with non-dihydropyridine calcium channel blockers (non-DHPs) might lead to an increase of systemic rivaroxaban exposure and anticoagulant effects in relation to the inhibition of metabolic enzymes and/or transporters by non-DHPs. This study was designed to evaluate the effects of verapamil and diltiazem on the pharmacokinetics and the prolongation of prothrombin time of rivaroxaban in rats. The data were analyzed using a pharmacokinetic/pharmacodynamics (PK/PD) modeling approach to quantify the influence of verapamil. Verapamil increased the systemic exposure of rivaroxaban by 2.8-fold (p <0.001) which was probably due to the inhibition of efflux transportation rather than metabolism. Prothrombin time was also prolonged in a proportional manner; diltiazem did not show any significant effects, however. A transit PK model in the absorption process comprehensively describes the double-peaks of rivaroxaban plasma concentrations and the corresponding change of prothrombin time with a simple linear relationship. The slope of prothrombin time vs. rivaroxaban plasma concentration in rats was retrospectively found to be insensitive by about 5.4-fold compared to than in humans. More than a 67% dose reduction in rivaroxaban is suggested in terms of both a pharmacokinetic point of view, and the sensitivity differences on the prolongation of prothrombin time when used concomitantly with verapamil.


PK/PD modeling; drug–drug interaction; prothrombin time; rivaroxaban; verapamil

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