Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of rivaroxaban
- Authors
- Kim, M.; Son, H.; Noh, K.; Kim, E.; Shin, B.; Kang, W.
- Issue Date
- Mar-2019
- Publisher
- MDPI AG
- Keywords
- Drug–drug interaction; PK/PD modeling; Prothrombin time; Rivaroxaban; Verapamil
- Citation
- Pharmaceutics, v.11, no.3, pp 1 - 10
- Pages
- 10
- Journal Title
- Pharmaceutics
- Volume
- 11
- Number
- 3
- Start Page
- 1
- End Page
- 10
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/36498
- DOI
- 10.3390/pharmaceutics11030133
- ISSN
- 1999-4923
1999-4923
- 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. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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