Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants

Abstract 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 effecti...

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Autores principales:	Holger Scheible, Martin Dyroff, Annick Seithel‐Keuth, Eleanor Harrison‐Moench, Nadra Mammasse, Andreas Port, Angelika Bachmann, Jennifer Dong, Jan Jaap vanLier, William Tracewell, David Mitchell
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/489421b638da46dbad0cbcea83c71c6e
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spelling	oai:doaj.org-article:489421b638da46dbad0cbcea83c71c6e2021-11-19T17:51:35ZEvobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants1752-80621752-805410.1111/cts.13108https://doaj.org/article/489421b638da46dbad0cbcea83c71c6e2021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13108https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract 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) 14C‐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.Holger ScheibleMartin DyroffAnnick Seithel‐KeuthEleanor Harrison‐MoenchNadra MammasseAndreas PortAngelika BachmannJennifer DongJan Jaap vanLierWilliam TracewellDavid MitchellWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2420-2430 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Holger Scheible Martin Dyroff Annick Seithel‐Keuth Eleanor Harrison‐Moench Nadra Mammasse Andreas Port Angelika Bachmann Jennifer Dong Jan Jaap vanLier William Tracewell David Mitchell Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants
description	Abstract 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) 14C‐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	article
author	Holger Scheible Martin Dyroff Annick Seithel‐Keuth Eleanor Harrison‐Moench Nadra Mammasse Andreas Port Angelika Bachmann Jennifer Dong Jan Jaap vanLier William Tracewell David Mitchell
author_facet	Holger Scheible Martin Dyroff Annick Seithel‐Keuth Eleanor Harrison‐Moench Nadra Mammasse Andreas Port Angelika Bachmann Jennifer Dong Jan Jaap vanLier William Tracewell David Mitchell
author_sort	Holger Scheible
title	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_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_sort	evobrutinib, a covalent bruton’s tyrosine kinase inhibitor: mass balance, elimination route, and metabolism in healthy participants
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/489421b638da46dbad0cbcea83c71c6e
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Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants

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