舒克度酮(KBP-5074)的体内外药动学及药物相互作用。

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Ping Wang, Jinrong Liu, Xiaojuan Tan, Fred Yang, James McCabe, Jay Zhang
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引用次数: 1

摘要

背景和目的:ocdurenone (KBP-5074)是一种新型的非甾体类矿物皮质激素受体拮抗剂,在临床试验中对未控制的高血压和3b/4期慢性肾病患者显示出安全性和有效性。本研究评估了细胞色素P450 (CYP)同工酶和药物转运体在鲨头二烯酮生物转化中的作用,以及鲨头二烯酮是否抑制或诱导了CYP酶和转运体。在健康志愿者中研究了舒克都乐酮与CYP3A抑制剂和诱导剂的临床药动学相互作用(DDI)。方法:通过体外实验确定哪些CYP酶参与了鲨头都烯酮的代谢,鲨头都烯酮是否抑制或诱导这些CYP酶;此外,还评估了章鱼酮对外排和摄取转运体的底物特性及其对主要药物转运体的抑制潜力。在健康志愿者中进行了一项临床DDI研究,以评估强CYP3A抑制剂(伊曲康唑)和诱导剂(利福平)对舒克都乐酮药代动力学的影响。结果:体外实验表明,叔都乐酮主要由CYP3A4代谢,对CYP3A4酶无抑制作用。Ocedurenone似乎是BCRP和P-gp外排转运蛋白的底物,并抑制BCRP、BSEP、MDR1、MATE1和2-K、OATP1B1/3和OCT1。临床DDI研究显示,伊曲康唑使舒克都酮口服清除率降低51%,使血浆浓度-时间曲线下面积(AUC0-inf)增加104%,而利福平使口服清除率提高6.4倍,使血浆AUC0-inf降低84%。结论:在临床有效剂量下,欧舒瑞酮是CYP3A底物,对主要药物代谢CYP酶和转运体无抑制潜力。吲哚醌对培养的人原代肝细胞CYP1A2和3A4活性无诱导作用。临床DDI研究表明,当单次0.5 mg剂量时,无论是单独给药还是与伊曲康唑或利福平一起给药时,奥克度萘酮的耐受性都很好,而伊曲康唑对奥克度萘酮的药代动力学影响较弱,而利福平对全身暴露的影响显著。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

Background and objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers.

Methods: In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics.

Results: The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%.

Conclusion: Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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