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Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.
Arthritis Res Ther. 2019 08 02; 21(1):183.AR

Abstract

BACKGROUND

The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.

METHODS

Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type.

RESULTS

Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees.

CONCLUSIONS

Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

Authors+Show Affiliations

Institute of Infection, Immunity and Inflammation, University of Glasgow, University Avenue, Glasgow, G128QQ, UK. Iain.McInnes@glasgow.ac.uk.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Primity Bio, Fremont, CA, USA.Eli Lilly and Company, Indianapolis, IN, USA.Eli Lilly and Company, Indianapolis, IN, USA.Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31375130

Citation

McInnes, Iain B., et al. "Comparison of Baricitinib, Upadacitinib, and Tofacitinib Mediated Regulation of Cytokine Signaling in Human Leukocyte Subpopulations." Arthritis Research & Therapy, vol. 21, no. 1, 2019, p. 183.
McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183.
McInnes, I. B., Byers, N. L., Higgs, R. E., Lee, J., Macias, W. L., Na, S., Ortmann, R. A., Rocha, G., Rooney, T. P., Wehrman, T., Zhang, X., Zuckerman, S. H., & Taylor, P. C. (2019). Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Research & Therapy, 21(1), 183. https://doi.org/10.1186/s13075-019-1964-1
McInnes IB, et al. Comparison of Baricitinib, Upadacitinib, and Tofacitinib Mediated Regulation of Cytokine Signaling in Human Leukocyte Subpopulations. Arthritis Res Ther. 2019 08 2;21(1):183. PubMed PMID: 31375130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. AU - McInnes,Iain B, AU - Byers,Nicole L, AU - Higgs,Richard E, AU - Lee,Jonathan, AU - Macias,William L, AU - Na,Songqing, AU - Ortmann,Robert A, AU - Rocha,Guilherme, AU - Rooney,Terence P, AU - Wehrman,Thomas, AU - Zhang,Xin, AU - Zuckerman,Steven H, AU - Taylor,Peter C, Y1 - 2019/08/02/ PY - 2018/12/17/received PY - 2019/07/22/accepted PY - 2019/8/4/entrez PY - 2019/8/4/pubmed PY - 2020/8/28/medline KW - Baricitinib KW - Cytokine KW - Janus kinase KW - Phosphorylated signal transducer and activator of transcription KW - Potency KW - Receptor kinase signaling KW - Rheumatoid arthritis KW - Selectivity KW - Tofacitinib KW - Upadacitinib SP - 183 EP - 183 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 21 IS - 1 N2 - BACKGROUND: The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. METHODS: Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. RESULTS: Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. CONCLUSIONS: Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/31375130/Comparison_of_baricitinib_upadacitinib_and_tofacitinib_mediated_regulation_of_cytokine_signaling_in_human_leukocyte_subpopulations_ L2 - https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-019-1964-1 DB - PRIME DP - Unbound Medicine ER -