Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Jämförelse av JAK-selektivitetsprofil med Upadacitinib

Någon jämförande studie har inte genomförts mellan baricitinib och upadacitinib.

JAK-STAT Pathway in Autoimmune Disorders

The JAK-STAT pathway is a key regulator of signaling from pro-inflammatory cytokines implicated in the pathogenesis of several autoimmune diseases.1 Inhibiting specific JAK-STAT pathways may reduce the activity of cytokines that signal through that pathway. 

Table 1. Cytokine Signaling Through JAK Pathways2,3

JAK Pairing

Cytokines Signaled

JAK1/JAK3

IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

JAK1/JAK2

IFN-γ

JAK1/TYK2

IL-10, IL-20, IL-22, IFNα, IFNβ

JAK2/TYK2

IL-12, IL-23

JAK1/JAK2 or TYK2

IL-6, IL-11, IL-27, CTF-1, CNTF, G-CSF, LIF, OSM

JAK2/JAK2

EPO, TPO, GM-CSF, GH, IL-3, IL-5

Abbreviations: CNTF = human ciliary neurotrophic factor; CTF-1= cardiotrophin 1; EPO = erythropoietin; G-CSF = granulocyte colony–stimulating factor; GH = growth hormone; GM-CSF = granulocyte-macrophage colony–stimulating factor; IFN = interferon; IL = interleukin; JAK = Janus kinase; LIF = leukemia inhibitory factor; OSM = oncostatin M; TPO = thrombopoietin; TYK = tyrosine kinase.

Janus Kinase Selectivity Profiles

Both baricitinib and upadacitinib are JAK inhibitors.4,5 Each has differing selectivities in JAK inhibition, which may result in subsequent differences in their effects on cytokine signaling.6

IC50 Definition

IC50 refers to the concentration of the compound that causes 50% inhibition of the enzyme activity. The lower the value of the IC50, the higher the potency of the inhibitory compound.7

JAK Selectivity 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 JAK3.8,9

For BARI, reported IC50 values are

  • 5.9 nM for JAK1

  • 5.7 nM for JAK2

  • >400 nM for JAK3, and

  • 53 nM for TYK2.10

JAK Selectivity of Upadacitinib

Upadacitinib is proposed to inhibit JAK1 and JAK2 at a higher selectivity than JAK3, and TYK2. Upadacitinib reported IC50 values are

  • 47 nM for JAK1

  • 120 nM for JAK2

  • 2304 nM for JAK3, and

  • 4690 nM for TYK2.11

Findings from phase 2 clinical studies of upadacitinib illustrate that upadacitinib may be more selective for JAK1 at lower doses and less selective at higher doses.5

Cytokine Signaling of Baricitinib and Upadacitinib Based on Ex vivo Comparisons

A comparison of the ex vivo pharmacologic profile of BARI and upadacitinib was conducted to assess the specific cytokines each compound modulates in the JAK-STAT pathway.12 See detailed results in Table 2.

Baricitinib Compared to Upadacitinib

The IC50 values for upadacitinib indicate higher potency compared to BARI toward inhibiting JAK1/3 signaling downstream of IL-2, 4, 15, and 21.12

Bacitinib and upadacitinib had similar potency for JAK1/2 dependent signaling by IL-6 and IFN-γ.12

Based on the results, the authors concluded that BARI and upadacitinib modulate distinct cytokine pathways to differing degrees and durations over 24 hours.12

Table 2. IC50 Values for Baricitinib and Upadacitinib in Cytokine-Stimulated Human Peripheral Blood Mononuclear Cell Preparations12


CD4+ T cells

CD4+ T cells

NK Cells

NK Cells

Monocytes

Monocytes

Stimulation/pSTAT

BARI (nM)

Upa (nM)

BARI (nM)

Upa (nM)

BARI (nM)

Upa (nM)

JAK1/3 dependent cytokines

IL-2/pSTAT5

29

10a

44

27b

NS

NS

IL-4/pSTAT6

48

18c

22

8b

45

22a

IL-15/pSTAT5

40

17c

67

40b

NS

NS

IL-21/pSTAT3

64

20c

62

24a

85

34

JAK2/2 or JAK2/TYK2 dependent cytokines

IL-3/pSTAT5

NS

NS

NS

NS

26

12b

G-CSF/pSTAT3

NS

NS

NS

NS

65

84

GM-CSF/pSTAT5

NS

NS

NS

NS

30

13c

JAK1/JAK2/TYK2 dependent cytokines

IL-6/pSTAT3

61

58

NS

NS

48

43

IL-10/pSTAT3

68

87

87

124

142

80c

IFN-γ/pSTAT1

NS

NS

NS

NS

38

30

IFN-α/pSTAT1

64

40

76

69

97

44a

IFN-α/pSTAT3

27

17

NS

NS

14

6b

IFN-α/pSTAT5

23

14

NS

NS

13

5a

Abbreviations: BARI = baricitinib; CD = cluster of differentiation; G-CSF = granulocyte-colony stimulating factor; IC50, = half maximum inhibitory concentration; IFN = interferon; IL = interleukin; JAK = Janus kinase; NK = natural killer; nM = nanomolar; NS = no stimulation; pSTAT = phosphorylated signal transducer and activator of transcription; TYK = tyrosine kinase; Upa = upadacitinib.

a p<.001 vs BARI.

b p<.01 vs BARI.

c p<.0001 vs BARI.

References

1. 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

2. O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007;44(10):2497-2506. http://dx.doi.org/10.1016/j.molimm.2006.11.025

3. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273-287. http://dx.doi.org/10.1111/j.1600-065X.2008.00754.x

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

5. Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol. 2016;68(12):2857-2866. http://dx.doi.org/10.1002/art.39808

6. O’Shea JJ, Schwartz DM, Villarino AV, et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-328. http://dx.doi.org/10.1146/annurev-med-051113-024537

7. Sinz, MW. Drug Metabolism in Preclinical Development. In: Krishna R, ed. Applications of Pharmacokinetic Principles in Drug Development: Principles in Drug Development. New York, NY: Springer Science & Business Media; 2004:75-132.

8. 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

9. 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

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

11. Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018;2:23. https://dx.doi.org/10.1186/s41927-018-0031-x

12. 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. https://dx.doi.org/10.1186/s13075-019-1964-1

Glossary

BARI = baricitinib

IC50 = inhibitory concentration of 50%

IFN = interferon

IL = interleukin

JAK = Janus kinase

STAT = signal transducers and activators of transcription

TYK = tyrosine kinase

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 M07 29

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