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