Year-end Sale % OFF 
Abstract
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.
Highlights
Rivaroxaban is a specific, competitive factor Xa inhibitor, directly acting on factor Xa
Rivaroxaban concentrations peaked in plasma 2.8 h after oral administration
Verapamil increased Cmax and AUC to infinite (AUCinf) of rivaroxaban by 2.9- (p < 0.01) and 2.8-fold (p < 0.001), respectively, and clearance decreased by 63%, compared with the control group
Summary
Rivaroxaban is a specific, competitive factor Xa inhibitor, directly acting on factor Xa. Concomitant use of rivaroxaban with these non-DHPs might lead to an increase in systemic rivaroxaban exposure and anticoagulant effects. When compared with rivaroxaban use alone, the adjusted incidence rate for major bleeding did not significantly increase when patients with non-valvular arterial fibrillation were treated with concurrent use of both drugs [8]. Concurrent use of both drugs in arterial fibrillation patients was not associated with an increased risk of stroke/non-CNS systemic embolism (p < 0.11), or non-major clinically relevant bleeding (p < 0.087), an increased risk of major bleeding and intracranial hemorrhage was strongly related [5]. A recent report outlined that in patients with mild renal insufficiency, verapamil increased the systemic exposure of rivaroxaban and bleeding risk so that modification of the recommended dosage was suggested [9]. Data were analyzed by using a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to quantify the influence of concurrent drugs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
