Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Jämförelse av JAK-selektivitetsprofilen med tofacitinib

Baricitinib och tofacitinib har inte studerats i några jämförande kliniska prövningar.

Comparison of Baricitinib and Tofacitinib

There have been no head to head clinical studies between baricitinib and tofacitinib.

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 disorders.1 Inhibiting specific JAK-STAT pathways may reduce the activity of cytokines that signal through that pathway.2

Table 1. Cytokine Signaling Through JAK Pathways3,4

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

Baricitinib and tofacitinib are both JAK inhibitors.5,6 Each has differing selectivities in JAK inhibition, which may result in subsequent differences in their effects on cytokine signaling.7

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.8

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 JAK3.9,10

For BARI, reported IC50 values are

  • 5.9 nM for JAK1

  • 5.7 nM for JAK2

  • >400 nM for JAK3, and

  • 53 nM for TYK2.6

JAK Selectivity of Tofacitinib

Tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TYK2. Tofacitinib reported IC50 values are

  • 3.2 nM for JAK1

  • 4.1 nM for JAK2

  • 1.6 nM for JAK3, and

  • 34.0 nM for TYK2.5,11

Cytokine Signaling of Baricitinib and Tofacitinib Based on Ex vivo Comparisons

A comparison of the ex vivo pharmacologic profile of BARI and tofacitinib 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 Tofacitinib

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

Bacitinib and tofacitinib had similar potency toward inhibiting JAK1/2 dependent signaling downstream of IL-6.12

Compared to tofacitinib IC50 values, BARI more potently inhibited

  • JAK1/TYK2 dependent signaling downstream of IFN-α, and

  • JAK2/2 dependent signaling downstream of GM-CSF.12

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

Table 2. IC50 Values for Baricitinib and Tofacitinib 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)

Tofa (nM)

BARI (nM)

Tofa (nM)

BARI (nM)

Tofa (nM)

JAK1/3 dependent cytokines

IL-2/pSTAT5

29

11a

44

15a

NS

NS

IL-4/pSTAT6

48

18a

22

8a

45

35b

IL-15/pSTAT5

40

15a

67

22a

NS

NS

IL-21/pSTAT3

64

22a

62

21a

85

37

JAK2/2 or JAK2/TYK2 dependent cytokines

IL-3/pSTAT5

NS

NS

NS

NS

26

102a

G-CSF/pSTAT3

NS

NS

NS

NS

65

97c

GM-CSF/pSTAT5

NS

NS

NS

NS

30

97a

JAK1/JAK2/TYK2 dependent cytokines

IL-6/pSTAT3

61

56

NS

NS

48

40

IL-10/pSTAT3

68

55

87

74

142

104b

IFN-γ/pSTAT1

NS

NS

NS

NS

38

46a

IFN-α/pSTAT1

64

132a

76

121a

97

163a

IFN-α/pSTAT3

27

51a

NS

NS

14

23a

IFN-α/pSTAT5

23

36c

NS

NS

13

22a

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; Tofa = tofacitinib; TYK = tyrosine kinase.

a p<.0001 vs BARI.

b p<.01 vs BARI.

c p<.001 vs BARI.

Inhibition Time by Baricitinib and Tofacitinib Doses

Levels of pSTAT were measured in cytokine-stimulated PBMCs from 6 healthy donors. Average daily percent inhibition of pSTAT (%SI) for selected cytokines was determined for BARI 2 mg once daily, BARI 4 mg once daily, tofacitinib 5 mg twice daily, and tofacitinib 10 mg twice daily  using calculated mean concentration time profiles over 24 hours.13,14

Overall, %SI in JAK2/2 or JAK2/Tyk2 cytokines were

  • higher for BARI 4 mg than tofacitinib 5 mg and 10 mg and 

  • similar for BARI 2 mg and tofacitinib 5 mg and 10 mg.13

Overall, %SI in JAK1/JAK2/Tyk2 cytokines were

  • higher for BARI 4 mg than tofacitinib 5 mg

  • similar for BARI 4 mg and tofacitinib 10 mg 

  • lower for BARI 2 mg than tofacitinib 10 mg, and 

  • similar for BARI 2 mg and tofacitinib 5 mg.13

Overall, %SI in JAK1/JAK3 cytokines were

  • lower for BARI 4 mg and 2 mg than tofacitinib 10 mg

  • similar for BARI 4 mg and tofacitinib 5 mg, and 

  • lower for BARI 2 mg than tofacitinib 5 mg and 10 mg.13

Neither BARI or tofacitinib continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. 13

Baricitinib and tofacitinib have different in vitro pharmacologic profiles and may modulate distinct cytokine pathways to differing degrees and durations over 24 hours.12,13

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’Shea JJ, Schwartz DM, Villarino AV, et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-28. http://dx.doi.org/10.1146/annurev-med-051113-024537

3. 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

4. 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

5. Xeljanz [summary of product characteristics]. Pfizer Europe MA EEIG.

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

7. 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

8. 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.

9. 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

10. 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

11. Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm. 2010;7(1):41. https://doi.org/10.1186/1476-9255-7-41

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

13. McInnes IB, Rocha G, Higgs RE, et al. Baricitinib, tofacitinib, upadacitinib, filgotinib, and cytokine signaling in human leukocyte subpopulations: an updated ex-vivo comparisons [abstract]. Ann Rheum Dis. 2020;79 (suppl 1):1. http://scientific.sparx-ip.net/archiveeular/?searchfor=McInnes&c=a&view=4&item=2020OP0001

14. McInnes IB, Rocha G, Higgs RE, et al. Baricitinib, tofacitinib, upadacitinib, filgotinib, and cytokine signaling in human leukocyte subpopulations: an updated ex-vivo comparisons. Poster presented at: The European League Against Rheumatism virtual Congress; June 3-6, 2020.

Glossary

BARI = baricitinib

GM-CSF = granulocyte/macrophage colony-stimulating factor

IC50 = inhibitory concentration of 50%

IFN = interferon

IL = interleukin

JAK = Janus kinase

PBMC = peripheral blood mononuclear cell

RA = rheumatoid arthritis

%SI = percent inhibition of pSTAT

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 2020 M05 04


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