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Filgotinib: A Clinical Pharmacology Review

Filgotinib (GS-6034, formerly GLPG0634; Jyseleca(®)) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK–signal transducer and activator of transcription pathway, which differ from those inhibited by...

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Autores principales: Namour, Florence, Anderson, Kacey, Nelson, Cara, Tasset, Chantal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249714/
https://www.ncbi.nlm.nih.gov/pubmed/35637376
http://dx.doi.org/10.1007/s40262-022-01129-y
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author Namour, Florence
Anderson, Kacey
Nelson, Cara
Tasset, Chantal
author_facet Namour, Florence
Anderson, Kacey
Nelson, Cara
Tasset, Chantal
author_sort Namour, Florence
collection PubMed
description Filgotinib (GS-6034, formerly GLPG0634; Jyseleca(®)) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK–signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9–10.7 h for filgotinib and 19.6–27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug–drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia’s correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan.
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spelling pubmed-92497142022-07-03 Filgotinib: A Clinical Pharmacology Review Namour, Florence Anderson, Kacey Nelson, Cara Tasset, Chantal Clin Pharmacokinet Review Article Filgotinib (GS-6034, formerly GLPG0634; Jyseleca(®)) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK–signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9–10.7 h for filgotinib and 19.6–27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug–drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia’s correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan. Springer International Publishing 2022-05-31 2022 /pmc/articles/PMC9249714/ /pubmed/35637376 http://dx.doi.org/10.1007/s40262-022-01129-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Review Article
Namour, Florence
Anderson, Kacey
Nelson, Cara
Tasset, Chantal
Filgotinib: A Clinical Pharmacology Review
title Filgotinib: A Clinical Pharmacology Review
title_full Filgotinib: A Clinical Pharmacology Review
title_fullStr Filgotinib: A Clinical Pharmacology Review
title_full_unstemmed Filgotinib: A Clinical Pharmacology Review
title_short Filgotinib: A Clinical Pharmacology Review
title_sort filgotinib: a clinical pharmacology review
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249714/
https://www.ncbi.nlm.nih.gov/pubmed/35637376
http://dx.doi.org/10.1007/s40262-022-01129-y
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