Utility of a physiologically-based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug-drug-disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice
Utility of a physiologically-based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug-drug-disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice
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DOI：
10.1002/bdd.1771
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发表时间：
2012-03-01
影响因子：
2.1
通讯作者：
Huang, Shiew-Mei
中科院分区：
文献类型：
--
作者：
Grillo, Joseph A.;Zhao, Ping;Huang, Shiew-Mei
背景：利伐沙班是一种口服Xa因子抑制剂。本次交流的主要目的是定量预测当不同程度肾损害的个体与另一种既是P-gp又是中度CYP 3A 4抑制剂的药物联合给药时，利伐沙班暴露量的变化。研究方法：开发了一种基于生理学的药代动力学（PBPK）模型，以模拟肾功能正常、轻度、中度和重度肾损害的年轻（20-45岁）或老年（55-65岁）受试者中利伐沙班的药代动力学，伴或不伴联合使用P-gp和中效CYP 3A 4抑制剂红霉素。结果：模拟表明，组合因素（即，肾损害和使用红霉素）对利伐沙班暴露的影响大于单独考虑这些因素的影响时的预期。与服用利伐沙班的正常年轻受试者相比，并发轻度、中度或重度肾损害加红霉素分别导致年轻受试者的暴露量增加1.9、2.4或2.6倍;老年受试者的暴露量增加2.5、2.9或3.0倍。结论：这些模拟表明，药物-药物-疾病相互作用是可能的，这可能会显著增加利伐沙班暴露并增加出血风险。这些模拟提供了关于可能结果的更多机制性见解，并允许人们决定在利伐沙班的批准产品标签中添加警示性语言。版权所有（C）2012约翰威利父子有限公司
Background: Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor. Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20-45 years) or older (55-65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin. Results: The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4- or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9-or 3.0-fold increase in exposure in older subjects. Conclusions: These simulations suggest that a drug-drug-disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright (C) 2012 John Wiley & Sons, Ltd.