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Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants
The highly selective, covalent Bruton’s tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well‐tolerated and effective. We un...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604242/ https://www.ncbi.nlm.nih.gov/pubmed/34374206 http://dx.doi.org/10.1111/cts.13108 |
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author | Scheible, Holger Dyroff, Martin Seithel‐Keuth, Annick Harrison‐Moench, Eleanor Mammasse, Nadra Port, Andreas Bachmann, Angelika Dong, Jennifer van Lier, Jan Jaap Tracewell, William Mitchell, David |
author_facet | Scheible, Holger Dyroff, Martin Seithel‐Keuth, Annick Harrison‐Moench, Eleanor Mammasse, Nadra Port, Andreas Bachmann, Angelika Dong, Jennifer van Lier, Jan Jaap Tracewell, William Mitchell, David |
author_sort | Scheible, Holger |
collection | PubMed |
description | The highly selective, covalent Bruton’s tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well‐tolerated and effective. We undertook a mass balance study in six men who received a single 75‐mg oral dose of evobrutinib containing ~ 3.6 MBq (100 μCi) (14)C‐evobrutinib, to determine the absorption, metabolic pathways, and routes of excretion of evobrutinib. The primary objectives of this phase I study (NCT03725072) were to (1) determine the rates and routes of total radioactivity excretion, including the mass balance of total drug‐related radioactivity in urine and feces, (2) assess the pharmacokinetics (PKs) of total radioactivity in blood and plasma, and (3) characterize the plasma PKs of evobrutinib. Exploratory end points included identifying and quantifying evobrutinib and its metabolites in plasma and excreta (urine and feces) and exploring key biotransformation pathways and clearance mechanisms. Evobrutinib was primarily eliminated in feces (arithmetic mean percentage, SD, 71.0, 2.1) and, to a lesser extent, in urine (20.6, 2.0), with most of the total radioactivity (85.3%) excreted in the first 72 h after administration. No unchanged evobrutinib was detected in excreta. Evobrutinib was rapidly absorbed and substantially metabolized upon absorption. Only one major metabolite M463‐2 (MSC2430422) was identified in plasma above the 10% of total drug exposure threshold, which classifies M463‐2 (MSC2430422) as a major metabolite according to the US Food and Drug Administration (FDA; metabolites in safety testing [MIST]) and the European Medicines Agency (EMA; International Conference on Harmonization [ICH] M3). These results support further development of evobrutinib and may help inform subsequent investigations. |
format | Online Article Text |
id | pubmed-8604242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86042422021-11-24 Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants Scheible, Holger Dyroff, Martin Seithel‐Keuth, Annick Harrison‐Moench, Eleanor Mammasse, Nadra Port, Andreas Bachmann, Angelika Dong, Jennifer van Lier, Jan Jaap Tracewell, William Mitchell, David Clin Transl Sci Research The highly selective, covalent Bruton’s tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well‐tolerated and effective. We undertook a mass balance study in six men who received a single 75‐mg oral dose of evobrutinib containing ~ 3.6 MBq (100 μCi) (14)C‐evobrutinib, to determine the absorption, metabolic pathways, and routes of excretion of evobrutinib. The primary objectives of this phase I study (NCT03725072) were to (1) determine the rates and routes of total radioactivity excretion, including the mass balance of total drug‐related radioactivity in urine and feces, (2) assess the pharmacokinetics (PKs) of total radioactivity in blood and plasma, and (3) characterize the plasma PKs of evobrutinib. Exploratory end points included identifying and quantifying evobrutinib and its metabolites in plasma and excreta (urine and feces) and exploring key biotransformation pathways and clearance mechanisms. Evobrutinib was primarily eliminated in feces (arithmetic mean percentage, SD, 71.0, 2.1) and, to a lesser extent, in urine (20.6, 2.0), with most of the total radioactivity (85.3%) excreted in the first 72 h after administration. No unchanged evobrutinib was detected in excreta. Evobrutinib was rapidly absorbed and substantially metabolized upon absorption. Only one major metabolite M463‐2 (MSC2430422) was identified in plasma above the 10% of total drug exposure threshold, which classifies M463‐2 (MSC2430422) as a major metabolite according to the US Food and Drug Administration (FDA; metabolites in safety testing [MIST]) and the European Medicines Agency (EMA; International Conference on Harmonization [ICH] M3). These results support further development of evobrutinib and may help inform subsequent investigations. John Wiley and Sons Inc. 2021-08-10 2021-11 /pmc/articles/PMC8604242/ /pubmed/34374206 http://dx.doi.org/10.1111/cts.13108 Text en © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics 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 | Research Scheible, Holger Dyroff, Martin Seithel‐Keuth, Annick Harrison‐Moench, Eleanor Mammasse, Nadra Port, Andreas Bachmann, Angelika Dong, Jennifer van Lier, Jan Jaap Tracewell, William Mitchell, David Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title | Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title_full | Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title_fullStr | Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title_full_unstemmed | Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title_short | Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants |
title_sort | evobrutinib, a covalent bruton’s tyrosine kinase inhibitor: mass balance, elimination route, and metabolism in healthy participants |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604242/ https://www.ncbi.nlm.nih.gov/pubmed/34374206 http://dx.doi.org/10.1111/cts.13108 |
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