Yiming Cheng, Xiaomin Wang, Liangang Liu, Jose Silva, Michael Thomas, Yan Li
{"title":"健康受试者体内[14C]-Iberdomide 的 I 期、开放标签、质量平衡研究。","authors":"Yiming Cheng, Xiaomin Wang, Liangang Liu, Jose Silva, Michael Thomas, Yan Li","doi":"10.1007/s13318-024-00886-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Iberdomide is a novel potent cereblon modulator (CELMoD<sup>®</sup>) 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.</p><p><strong>Method: </strong>After a single dose of radiolabelled [<sup>14</sup>C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments.</p><p><strong>Results: </strong>Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [<sup>14</sup>C]-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<sub>0-24</sub>]), 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%).</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration number: </strong>NCT03294603.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"355-365"},"PeriodicalIF":1.9000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Phase I, Open-Label, Mass Balance Study of [<sup>14</sup>C]-Iberdomide in Healthy Subjects.\",\"authors\":\"Yiming Cheng, Xiaomin Wang, Liangang Liu, Jose Silva, Michael Thomas, Yan Li\",\"doi\":\"10.1007/s13318-024-00886-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Iberdomide is a novel potent cereblon modulator (CELMoD<sup>®</sup>) 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.</p><p><strong>Method: </strong>After a single dose of radiolabelled [<sup>14</sup>C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments.</p><p><strong>Results: </strong>Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [<sup>14</sup>C]-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<sub>0-24</sub>]), 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%).</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration number: </strong>NCT03294603.</p>\",\"PeriodicalId\":11939,\"journal\":{\"name\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"volume\":\" \",\"pages\":\"355-365\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13318-024-00886-4\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/23 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-024-00886-4","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/23 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
A Phase I, Open-Label, Mass Balance Study of [14C]-Iberdomide in Healthy Subjects.
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 [AUC0-24]), 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.
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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