A Phase I, Open-Label, Mass Balance Study of [¹⁴C]-Iberdomide in Healthy Subjects.

IF 1.9 4区医学 Q3 PHARMACOLOGY & PHARMACY

European Journal of Drug Metabolism and Pharmacokinetics Pub Date : 2024-05-01 Epub Date: 2024-03-23 DOI:10.1007/s13318-024-00886-4

Yiming Cheng, Xiaomin Wang, Liangang Liu, Jose Silva, Michael Thomas, Yan Li

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引用次数: 0

Abstract

Background: Iberdomide is a novel potent cereblon modulator (CELMoD^®) agent, which is currently under clinical development for hematological malignancies. A human mass balance study was conducted to characterize the biotransformation and excretion pathways of iberdomide.

Method: After a single dose of radiolabelled [¹⁴C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments.

Results: Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [¹⁴C]-iberdomide-derived radioactivity in humans was 45.9% in urine and 42.6% in feces. Based on exposure (area under the concentration-time curve [AUC_0-24]), iberdomide and M12 (metabolites) accounted for approximately 59% and 14% of circulating total radioactivity (TRA) exposure, respectively. Of the 88.5% TRA excreted, approximately 27% was excreted as unchanged iberdomide and 62% as metabolites, with similar amounts of excreted metabolites in the urine (16%) and feces (11%).

Conclusion: Biotransformation of iberdomide in humans included multiple oxidations of the morpholino moiety as well as glutarimide ring hydrolysis of parent and oxidized metabolites and a combination of these pathways. Iberdomide was the predominant component in human plasma, with metabolite M12 being the most prominent circulating metabolite. In excreta, similar iberdomide-derived radioactivity was found in urine and feces.

Trial registration number: NCT03294603.

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健康受试者体内[14C]-Iberdomide 的 I 期、开放标签、质量平衡研究。

背景：伊伯多米德是一种新型强效脑龙调节剂（CELMoD®），目前正处于治疗血液恶性肿瘤的临床开发阶段。为了确定伊伯多米德的生物转化和排泄途径，我们进行了一项人体质量平衡研究：方法：6 名健康受试者在服用单剂量放射性标记的 [14C]-iberdomide （1 毫克）后。收集血液、尿液和粪便样本，进行药代动力学、质量平衡和临床实验室评估：结果表明，健康受试者对单次口服 1 毫克 iberdomide 的耐受性普遍良好。人体尿液中[14C]-iberdomide 衍生放射性的回收率为 45.9%，粪便中的回收率为 42.6%。根据暴露量（浓度-时间曲线下面积 [AUC0-24]），伊伯多米和 M12（代谢物）分别约占循环总放射性（TRA）暴露量的 59% 和 14%。在88.5%的TRA排泄量中，约27%以未改变的伊伯多米德形式排泄，62%以代谢物形式排泄，尿液（16%）和粪便（11%）中的代谢物排泄量相似：结论：伊博多肽在人体中的生物转化包括吗啉基的多重氧化、母体和氧化代谢物的戊二酰亚胺环水解以及这些途径的组合。伊伯多米德是人体血浆中的主要成分，代谢物 M12 是最主要的循环代谢物。在排泄物中，尿液和粪便中也发现了类似的伊伯多米德衍生放射性：试验注册号：NCT03294603。

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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来源期刊

European Journal of Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

3.70

自引率

0.00%

发文量

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.