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First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator
Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC‐220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single‐dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple‐dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246954/ https://www.ncbi.nlm.nih.gov/pubmed/32969202 http://dx.doi.org/10.1002/cpdd.869 |
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author | Ye, Ying Gaudy, Allison Schafer, Peter Thomas, Michael Weiss, Daniel Chen, Nianhang Liu, Liangang Xue, Yongjun Carayannopoulos, Leon Palmisano, Maria |
author_facet | Ye, Ying Gaudy, Allison Schafer, Peter Thomas, Michael Weiss, Daniel Chen, Nianhang Liu, Liangang Xue, Yongjun Carayannopoulos, Leon Palmisano, Maria |
author_sort | Ye, Ying |
collection | PubMed |
description | Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC‐220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single‐dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple‐dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7‐day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose‐proportional manner. Terminal half‐life was 9‐13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (E(max), 92.4%; EC(50), 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (E(max), 34.8%; EC(50), 0.932 ng/mL). Lipopolysaccharide‐stimulated proinflammatory cytokines (IL‐1α, IL‐1β) were reduced, but anti‐CD3‐stimulated IL‐2 and interferon‐γ were increased. Iberdomide 1 mg once daily partially decreased T‐cell‐independent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose‐dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7‐day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted. |
format | Online Article Text |
id | pubmed-8246954 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82469542021-07-02 First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator Ye, Ying Gaudy, Allison Schafer, Peter Thomas, Michael Weiss, Daniel Chen, Nianhang Liu, Liangang Xue, Yongjun Carayannopoulos, Leon Palmisano, Maria Clin Pharmacol Drug Dev Articles Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC‐220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single‐dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple‐dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7‐day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose‐proportional manner. Terminal half‐life was 9‐13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (E(max), 92.4%; EC(50), 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (E(max), 34.8%; EC(50), 0.932 ng/mL). Lipopolysaccharide‐stimulated proinflammatory cytokines (IL‐1α, IL‐1β) were reduced, but anti‐CD3‐stimulated IL‐2 and interferon‐γ were increased. Iberdomide 1 mg once daily partially decreased T‐cell‐independent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose‐dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7‐day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted. John Wiley and Sons Inc. 2020-09-23 2021-05 /pmc/articles/PMC8246954/ /pubmed/32969202 http://dx.doi.org/10.1002/cpdd.869 Text en © 2020 Bristol Myers Squibb. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Ye, Ying Gaudy, Allison Schafer, Peter Thomas, Michael Weiss, Daniel Chen, Nianhang Liu, Liangang Xue, Yongjun Carayannopoulos, Leon Palmisano, Maria First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title | First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title_full | First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title_fullStr | First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title_full_unstemmed | First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title_short | First‐in‐Human, Single‐ and Multiple‐Ascending‐Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator |
title_sort | first‐in‐human, single‐ and multiple‐ascending‐dose studies in healthy subjects to assess pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide, a novel cereblon e3 ligase modulator |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246954/ https://www.ncbi.nlm.nih.gov/pubmed/32969202 http://dx.doi.org/10.1002/cpdd.869 |
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