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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...

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Autores principales: Ye, Ying, Gaudy, Allison, Schafer, Peter, Thomas, Michael, Weiss, Daniel, Chen, Nianhang, Liu, Liangang, Xue, Yongjun, Carayannopoulos, Leon, Palmisano, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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.
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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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