Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Smärtlindrande verkningsmekanism

Det är inte känt vad som exakt är den smärtlindrande verkningsmekanismen hos baricitinib på patienter med reumatoid artrit.

The Role of Cytokines and JAKs in Inflammation

Many pro-inflammatory cytokines require members of the JAK family of protein tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) to transduce signals across cell membranes.1-4

Inside the cell, JAKs facilitate the transfer of a phosphate group from ATP to STATs via autophosphorylation and transphosphorylation.4 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.1,4-6

The inhibition of one or more JAKs modulates the activity of the associated JAK-dependent cytokines.2,3

In addition to inflammation, there is evidence the JAK-STAT pathway contributes to pain response by facilitating the signaling of pronociceptive cytokines.7,8

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 JAK3.2,3

Baricitinib modulates the JAK-STAT pathway, and, consequently, signaling by cytokines including IL-6, by transiently occupying the ATP binding pocket of the JAK. This inhibits the phosphorylation of JAKs and the subsequent phosphorylation and activation of STATs, including STAT3 a key mediator of chronic inflammation.3,4,7

Janus kinase inhibition by BARI is transient and reversible.2 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.2

Potential Mechanism of the Effects of Baricitinib on Pain

Improvements in patient-reported pain were observed in the BARI treatment groups across the phase 3 RA clinical studies.9-12

The exact mechanism of how BARI improves pain in RA patients is unknown. However, a study in rats was conducted to determine if BARI's inhibition of JAKs, including JAK1 and JAK2, could reduce joint pain and gait impairment in an inflammagen-induced rodent model.13

In Sprague Dawley rats, unilateral joint injury was induced via intra-articular injection of Complete Freunds Adjuvant. The rats were treated with vehicle, positive control (tramadol 40 mg/kg), or BARI 1, 3, or 10 mg/kg via oral administration. Gait assessment was done via treadmill at baseline and over 3 days post-injection. Total STAT3 and phospho-STAT3 protein levels were examined from dorsal root ganglion harvested after completion of gait assessment.13

Treatment with BARI significantly

  • decreased phospho-STAT3 protein levels in a dose-dependent manner, starting at the 3 mg/kg dose with a maximal response at the 10 mg/kg doses (p<.01 for both), and

  • improved composite gait score at the 10 mg/kg dose (p<.05) by day 3.13

No changes were observed in total STAT3 protein levels with BARI treatment.13

The pharmacodynamic inhibition of JAK-STAT signaling in the dorsal root ganglion correlated with attenuation of joint deficits observed with BARI treatment in this rodent model.13

Molecular Description

Baricitinib has

  • an empirical formula of C16H17N7O2S,

  • a molecular weight of 371.42, and 

  • the structural formula as shown in Figure 1.14

Figure 1. Baricitinib Structural Formula14

 

Information from the label

Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs. Baricitinib may be used as monotherapy or in combination with methotrexate.15

References

1. 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

2. 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

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. 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

5. 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

6. 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

7. Busch-Dienstfertig M, Gonzalez-Rodriguez S. IL-4, JAK-STAT signaling, and pain [published online January 2, 2014]. JAKSTAT. http://dx.doi.org/10.4161/jkst.27638

8. Salaffi F, Giacobazzi G, Di Carol M. Chronic pain in inflammatory arthritis: mechanisms, metrology, and emerging targets- a focus on the JAK-STAT pathway [published online February 7, 2018]. Pain Res Manag. http://dx.doi.org/10.1155/2018/8564215

9. Emery P, Blanco R, Maldonado Cocco J, et al. Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis. RMD Open. 2017;3(1):e000410. http://dx.doi.org/10.1136/rmdopen-2016-000410

10. Keystone EC, Taylor PC, Tanaka Y, et al. Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: Secondary analyses from the RA-BEAM study. Ann Rheum Dis. 2017;76(11):1853-1861. http://dx.doi.org/10.1136/annrheumdis-2017-211259

11. Schiff M, Takeuchi T, Fleischmann R, et al. Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Res Ther. 2017;19(1):208. https://doi.org/10.1186/s13075-017-1410-1

12. Smolen JS, Kremer JM, Gaich CL, et al. Patient-reported outcomes from a randomized phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis. 2017;76(4):694-700. http://dx.doi.org/10.1136/annrheumdis-2016-209821

13. Knopp KL, Kato A, Wall TM, et al. Baricitinib improves joint mobility after injury in a rodent forced-ambulation model. Ann Rheum Dis. 2019;78(2):1089. http://dx.doi.org/10.1136/annrheumdis-2019-eular.1751.

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

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

Glossary

ATP = adenosine triphosphate

BARI = baricitinib

DNA = deoxyribonucleic acid

IC50 = inhibitory concentration of 50%

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 2019 M02 12


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