基于生理学的药代动力学模型预测恩扎鲁胺与P-gp和CYP3A联合底物的药物相互作用。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2023-10-01 Epub Date: 2023-06-21 DOI:10.1007/s10928-023-09867-7
Yukio Otsuka, Srinivasu Poondru, Peter L Bonate, Rachel H Rose, Masoud Jamei, Fumihiko Ushigome, Tsuyoshi Minematsu
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引用次数: 0

摘要

已知恩扎鲁胺能强烈诱导细胞色素P4503A4(CYP3A4)。此外,恩扎鲁胺在体外研究中显示出对P-糖蛋白(P-gp)的诱导和抑制作用。恩扎鲁胺与地高辛(一种典型的P-gp底物)之间的临床药物相互作用(DDI)研究表明,恩扎鲁酰胺对P-gp底物的抑制作用较弱。直接口服抗凝剂(DOAC),如阿哌沙班和利伐沙班,是CYP3A4和P-gp的双重底物,因此建议避免将这些DOAC与P-gp和强CYP3A诱导剂联合给药。恩扎鲁胺对阿哌沙班和利伐沙班血浆暴露的P-gp和CYP3A的净影响是治疗前列腺癌症静脉血栓栓塞患者的医生感兴趣的。因此,进行了基于生理学的药代动力学(PBPK)分析,以预测在存在160 mg恩扎鲁胺每日一次给药的情况下阿哌沙班和利伐沙班暴露的DDI的幅度。恩扎鲁胺和M2的PBPK模型被开发并验证为CYP3A和P-gp介导的相互作用的肇事者,M2是恩扎鲁酰胺的主要代谢产物,也有可能诱导CYP3A和P-gp并抑制P-gp。模拟结果预测,当160 mg多剂量恩扎鲁胺联合给药时,阿哌沙班的AUC下降31%,Cmax没有变化,利伐沙班的AUC下降45%,Cmax下降25%。总之,恩扎鲁胺被认为通过CYP3A诱导和净P-gp抑制的联合作用来减少阿哌沙班和利伐沙班的暴露。同时使用这些药物需要仔细监测疗效和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.

Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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