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

Scheible, Holger; Dyroff, Martin C.; Seithel-Keuth, Annick; Harrison-Moench, Eleanor; Mammasse, Nadra; Port, Andreas; Bachmann, Angelika; Dong, Jennifer Q.; Lier, Jan Jaap van; Tracewell, William; Mitchell, David

doi:10.1111/cts.13108

Cited by 11 publications

(6 citation statements)

References 25 publications

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“…The results indicate that a high dose has an effect over a low dose. The explanation may point to the dose-dependent character of TKI occupancy, such as single evobrutinib doses of greater than or equal to 100 mg with more than 50% of TKI occupancy ( 28 ). Similarly, tolebrutinib at 60 mg/day has been confirmed to be effective in reducing gadolinium-enhancing lesions ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…Because of its pharmacokinetic features, evobrutinib may not reduce the relapse rate. Evobrutinib's superiority for MS remission may be limited by its short half-life of 2 h and 85.3% excretion in the first 72 h after administration ( 28 ). Masitinib, which has been proven to maintain remission of mastocytosis for over two years, still has no specific explanation.…”

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of tyrosine kinase inhibitors for the treatment of multiple sclerosis: A systematic review and meta-analysis from randomized controlled trials

Yan

Wang

et al. 2022

Front. Neurol.

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BackgroundMultiple sclerosis (MS), an autoimmune disease, is characterized by inflammatory demyelinating lesions in the white matter of the central nervous system. Drugs targeting tyrosine kinase, a critical component of immune cell receptor signaling, have been developed to treat MS. However, the exact efficacy and safety of tyrosine kinase inhibitors (TKIs) are still controversial, and comprehensive analysis with a high level of evidence is needed.MethodsMedline, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials (RCTs) evaluating TKIs versus placebo for MS were searched up to April 1st, 2022. The risk ratio (RR) and mean difference (MD) or standard mean difference (SMD) were analyzed using dichotomous outcomes and continuous outcomes, respectively, with a random effect model.ResultsA total of 1,043 patients derived from four clinical trials were included to investigate the efficacy and safety of TKI therapy for MS. According to our analysis, TKIs decreased the cumulative number of gadolinium-enhancing lesions on T1-weighted MRI with the application of high dose (SMD = −0.61, 95% CI: −0.93 to −0.30, P = 0.0001). Meanwhile, TKIs prevented the expanded disability status scale (EDSS) from rising (MD = −0.10, 95% CI: −0.19 to −0.00, P = 0.046). In terms of MS relapse, TKIs have not revealed an obvious statistical difference compared with placebo (RR = 0.96, 95% CI: 0.55–1.65, P = 0.8755). However, more adverse events seem to occur in the TKIs group, both for adverse events (RR = 1.12, 95% CI: 1.05–1.19, P = 0.0009) and serious adverse events (RR = 1.91, 95% CI: 1.30–2.81, P = 0.001).ConclusionTyrosine kinase inhibitors have shown promise in treating MS. Generally, TKIs that attain the effective dose demonstrate definite efficacy and have tolerable side effects. More clinical trials and validation are needed, and we anticipate that TKIs will be a viable alternative for MS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of tyrosine kinase inhibitors for the treatment of multiple sclerosis: A systematic review and meta-analysis from randomized controlled trials

Yan

Wang

et al. 2022

Front. Neurol.

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“…This is based on the knowledge that several covalent KIs of the acrylamide class are metabolized to epoxides, for example evobrutinib generates a diol (Chart 1), clearly indicating initial formation of an epoxide and thus making "acrylamide" a SARM. 27 There have been reports on RM formation from sunitinib via oxidative defluorination (SMARTS name "4-F-Benzene-N"). 26,28,29 Another alert in SpotRM warns for the presence of "5m-N-heterocycles with 3-alkyl", which could lead to methides on the pyrrole.…”

Section: Conceptmentioning

confidence: 99%

“…Instead, it anticipates the possibility of CYP oxidation of the double bond resulting in a reactive epoxide. This is based on the knowledge that several covalent KIs of the acrylamide class are metabolized to epoxides, for example evobrutinib generates a diol (Chart ), clearly indicating initial formation of an epoxide and thus making “acrylamide” a SARM …”

Section: Work To Extend and Improve The Sarm Conceptmentioning

confidence: 99%

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM

Claesson

2024

Chem. Res. Toxicol.

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Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

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“…Evobrutinib (A18, M2951, Merck, Readington Township, NJ, USA) is a highly selective, irreversible, covalent BTKi inhibitor (Cys481 IC50 = 9 nM) with high selectivity in inhibiting both BCR and Fc receptor signaling [ 29 , 53 ]. Evobrutinib inhibits B-cell activation and differentiation, as well as M1 macrophage polarization.…”

Section: Characteristics Of Btk Inhibitorsmentioning

confidence: 99%

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Robak

2022

JCM

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.

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

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 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.

Cited by 11 publications

References 25 publications

Safety and efficacy of tyrosine kinase inhibitors for the treatment of multiple sclerosis: A systematic review and meta-analysis from randomized controlled trials

Safety and efficacy of tyrosine kinase inhibitors for the treatment of multiple sclerosis: A systematic review and meta-analysis from randomized controlled trials

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

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