Kim Minsoo, Son Heebin, Noh Keumhan, Kim Eunyoung, Shin Beom Soo, Kang Wonku
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.
Pharmaceutics. 2019 Mar 19;11(3):133. doi: 10.3390/pharmaceutics11030133.
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 ( <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.
利伐沙班与非二氢吡啶类钙通道阻滞剂（非DHPs）合用可能会导致利伐沙班全身暴露量增加以及抗凝作用增强，这与非DHPs对代谢酶和/或转运蛋白的抑制作用有关。本研究旨在评估维拉帕米和地尔硫䓬对大鼠体内利伐沙班的药代动力学及凝血酶原时间延长的影响。采用药代动力学/药效学（PK/PD）建模方法对数据进行分析，以量化维拉帕米的影响。维拉帕米使利伐沙班的全身暴露量增加了2.8倍（<0.001），这可能是由于对流出转运的抑制而非代谢。凝血酶原时间也呈比例延长；然而，地尔硫䓬未显示出任何显著影响。吸收过程中的转运PK模型以简单的线性关系全面描述了利伐沙班血浆浓度的双峰以及凝血酶原时间的相应变化。回顾性发现，与人类相比，大鼠凝血酶原时间与利伐沙班血浆浓度的斜率不敏感约5.4倍。从药代动力学角度以及与维拉帕米合用时凝血酶原时间延长的敏感性差异来看，建议利伐沙班剂量降低超过67%。
