Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Verkningsmekanism

Baricitinib är en selektiv och reversibel hämmare av JAK-familjen av proteintyrosinkinaser, särskilt JAK1 och JAK2.

Information from the label

Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50 values of 5.9, 5.7, 53 and > 400 nM, respectively.1

Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.1

The Role of Cytokines and JAKs in Rheumatoid Arthritis

Rheumatoid arthritis is associated with an abnormal production of pro-inflammatory cytokines and growth factors.2-4 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.3,5-7

Inside the cell, JAKs facilitate the transfer of a phosphate group from ATP to STATs via autophosphorylation and transphosphorylation.7 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.5,7-9

The inhibition of one or more JAKs modulates the activity of the associated JAK-dependent cytokines.3,6

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 JAK3.3,6

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.7 

Janus kinase inhibition by BARI is transient and reversible.6 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.3 

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.6

Description

Baricitinib has

  • an empirical formula of C16H17N7O2S,

  • a molecular weight of 371.42, and 

  • the structural formula as shown in Figure 1.10

Figure 1. Baricitinib Structural Formula10

 

References

1. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Malemud 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

3. Shi 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 Pharm. 2014;54(12):1354-1361. http://dx.doi.org/10.1002/jcph.354

4. Mateen 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

5. Pesu 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

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

7. Schwartz 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

8. Villarino 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

9. O'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

10. Data 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

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2018 M03 22


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