JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib

ObjectiveJanus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmaco...

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Veröffentlicht in:Annals of the rheumatic diseases Jg. 80; H. 7; S. 865 - 875
Hauptverfasser: Traves, Paqui G, Murray, Bernard, Campigotto, Federico, Galien, René, Meng, Amy, Di Paolo, Julie A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Elsevier Limited 01.07.2021
BMJ Publishing Group
Schlagworte:
Adverse events
Antirheumatic Agents - pharmacology
Arthritis, Rheumatoid
Azetidines - pharmacology
Cells, Cultured
Clinical medicine
Colonies
Colony-stimulating factor
Cytokines
Cytokines - drug effects
Flow cytometry
Granulocyte-macrophage colony-stimulating factor
Granulocytes
Heterocyclic Compounds, 3-Ring - pharmacology
Homeostasis
Humans
Interleukin 12
Interleukin 15
Interleukin 2
Interleukin 23
Interleukin 4
Interleukin 6
Janus kinase
Janus kinase 2
Janus Kinase Inhibitors - pharmacology
Janus Kinases - drug effects
Kinases
Leukocytes (mononuclear)
Peripheral blood mononuclear cells
Pharmacodynamics
Pharmacokinetics
Phosphorylation
Piperidines - pharmacology
Plasma
Protein-tyrosine kinase
Purines - pharmacology
Pyrazoles - pharmacology
Pyridines - pharmacology
Pyrimidines - pharmacology
Rheumatoid Arthritis
Signal transduction
Sulfonamides - pharmacology
Transcription
Triazoles - pharmacology
α-Interferon
γ-Interferon
Japan
cytokines
arthritis
antirheumatic agents
rheumatoid
immune system diseases
ISSN:0003-4967, 1468-2060, 1468-2060
Online-Zugang:Volltext
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Zusammenfassung:ObjectiveJanus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.MethodsIn vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.ResultsJAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.ConclusionFilgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0003-4967
1468-2060
1468-2060
DOI:10.1136/annrheumdis-2020-219012