Olumiant® (Baricitinib)

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Baricitinib: Mechanism of Action in Rheumatoid Arthritis

Baricitinib is a selective and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK2. Approved Audience

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The Role of Cytokines and JAKs in Rheumatoid Arthritis

Rheumatoid arthritis is associated with an abnormal production of pro-inflammatory cytokines and growth factors.1-3 Many pro-inflammatory cytokines, including IL-2, IL-6, IL-12, IFN-alpha, IFN-beta, and IFN-gamma, and GM-CSF, require members of the JAK family of protein tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) to transduce signals across cell membranes.2,4-6

Inside the cell, JAKs facilitate the transfer of a phosphate group from ATP to STATs via autophosphorylation and transphosphorylation.6 This reversible phosphorylation activates the STATs and allows them to

  • move to the nucleus of the cell, bind to DNA and other gene regulatory proteins, and
  • activate the transcription of genes involved in inflammation.4,6-8

The inhibition of one or more JAKs modulates the activity of the associated JAK-dependent cytokines.2,5

Mechanism of Action of Baricitinib

Baricitinib is a selective and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK2, with less selectivity for TYK2 and JAK3.2,5

Baricitinib modulates the JAK-STAT pathway, and, consequently, signaling by cytokines including IL-6, IFN, and GM-CSF, by transiently occupying the ATP binding pocket of the JAK. This inhibits the phosphorylation of JAKs and the subsequent phosphorylation and activation of STATs.6 

Janus kinase inhibition by BARI is transient and reversible.5 Baricitinib inhibits signaling through the JAK-STAT pathway for a portion of the day. Maximal inhibition occurs at 1 to 2 hours postdose and returns to baseline by 16 to 24 hours.2 

In isolated enzyme assays, BARI exhibited

  • selectivity for JAK1 with an IC50 of 5.9 nM and JAK2 with an IC50=5.7 nM,
  • 100-fold less selectivity for JAK3 with an approximate IC50  of 560 nM, and
  • 10-fold less selectivity for TYK2 with an IC50 of 53 nM.5

Mechanism of Action Video

A detailed visual representation of the mechanism of action of BARI may be accessed via the video link in the figure below VIDEO: Mechanism of Action of Baricitinib in RA.

VIDEO: Mechanism of Action of Baricitinib in RA

Abbreviations: GM-CSF = granulocyte-macrophage colony-stimulating factor; JAK = janus kinase; IL = interleukin; TYK = tyrosine kinase.

Description

Baricitinib has

Baricitinib Structural Formula9

References

1Malemud CJ, Pearlman E. Targeting JAK/STAT signaling pathway in inflammatory diseases. Curr Signal Transduct Ther. 2009;4(3):201-221. http://dx.doi.org/10.2174/157436209789057467

2Shi JG, Chen X, Lee F, et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol. 2014;54(12):1354-1361. http://dx.doi.org/10.1002/jcph.354

3Mateen S, Zafar A, Moin S, et al. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chimica Acta. 2016;455:161-171. http://dx.doi.org/10.1016/j.cca.2016.02.010

4Pesu M, Laurence A, Kishore N, et al. Therapeutic targeting of Janus kinases. Immunol Rev. 2008;223(1):132-142. http://dx.doi.org/10.1111/j.1600-065X.2008.00644.x

5Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

6Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25-36. http://dx.doi.org/10.1038/nrrheum.2015.167

7Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol. 2015;194(1):21-27. http://dx.doi.org/10.4049/jimmunol.1401867

8O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161-170. http://dx.doi.org/10.1056/NEJMra1202117

9Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

ATP = adenosine triphosphate

BARI = baricitinib

DNA = deoxyribonucleic acid

GM-CSF = granulocyte/macrophage colony-stimulating factor

IC50 = inhibitory concentration of 50%

IFN = interferon

IL = interleukin

JAK = Janus kinase

RA = rheumatoid arthritis

TYK = tyrosine kinase

STAT = signal transducers and activators of transcription

Fecha de la última revisión: 2021 M02 15


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