Olumiant ® (baricitinib) tabletter

För fullständig produktresumé för Olumiant se FASS.

Denna information är endast avsedd för sjukvårdspersonal verksam i Sverige och som svar på din fråga. Informationen nedan är på engelska

Hur fungerar Olumiant® (baricitinib) vid atopisk dermatit?

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

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Baricitinib Label Information Related to Mechanism of Action

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 Atopic Dermatitis

Atopic dermatitis is an immune-driven disease. It is characterized by acute recurring flares or relapses on a background of chronic defects in epidermal barrier function combined with abnormal immune responsiveness in the skin.2

The inflammatory response in atopic dermatitis is typified by the activation of

  • Th2 cells
  • Th22 cells
  • keratinocytes, and
  • Langerhans cells.3,4

Atopic dermatitis is associated with elevated levels of multiple cytokines including IL-4, IL-5, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin.3,4 Upon activation and differentiation of Th2, cytokines such as IL-4 and IL-5, require members of the JAK family of protein tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) to transduce signals across cell membranes. 5-8

Inside the cell, JAKs facilitate the transfer of a phosphate group from ATP to STATs via autophosphorylation and transphosphorylation.8 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.6,8-10

The inhibition of one or more JAKs modulates the activity of the associated JAK-dependent cytokines.7,11

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 JAK3.7,11

Baricitinib modulates the JAK-STAT pathway, and, consequently, signaling by cytokines, by transiently occupying the ATP binding pocket of the JAK. This inhibits the phosphorylation of JAKs and the subsequent phosphorylation and activation of STATs.8 

Janus kinase inhibition by BARI is transient and reversible.11 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.7 

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.11

Description

Baricitinib has

Baricitinib Structural Formula12

 

References

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

2Leung DY. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int. 2013;62(2):151-61. http://dx.doi.org/10.2332/allergolint.13-RAI-0564

3He R and Geha RS. Thymic stromal lymphopoietin. Ann N Y Acad Sci. 2010;1183:13-24. http://dx.doi.org/10.1111/j.1749-6632.2009.05128.x

4Brunner PM, Guttman-Yassky E, and Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139(4):S65-76. http://dx.doi.org/10.1016/j.jaci.2017.01.011

5Bao L, Zhang H, and Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAK-STAT. 2013;2(3):e24137. https://doi.org/10.4161/jkst.24137

6Pesu 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

7Shi 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

8Schwartz 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

9Villarino 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

10O'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

11Fridman 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

12Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AD = atopic dermatitis

ATP = adenosine triphosphate

BARI = baricitinib

DNA = deoxyribonucleic acid

IC50 = inhibitory concentration of 50%

IL = interleukin

JAK = Janus kinase

STAT = signal transducers and activators of transcription

Th = T-helper

TYK = tyrosine kinase

Datum fӧr senaste ӧversyn 2019 M02 11


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