Mechanism of Action of Rinvoq (Upadacitinib)
Upadacitinib is a selective Janus kinase (JAK) inhibitor that primarily targets JAK1, modulating intracellular signaling pathways involved in immune-mediated inflammatory diseases. 1
Primary Mechanism
- Upadacitinib inhibits JAK enzymes, which are intracellular enzymes that transmit signals from cytokine or growth factor receptors on the cellular membrane 1
- Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs), which modulate intracellular activity including gene expression 1
- Upadacitinib prevents the phosphorylation and activation of STATs by inhibiting JAKs, thereby interrupting this signaling cascade 1
Selectivity Profile
- In cell-free isolated enzyme assays, upadacitinib demonstrates greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2 1
- In human leukocyte cellular assays, upadacitinib inhibits cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2 mediated STAT phosphorylation 1, 2
- At clinically used doses, upadacitinib functions primarily as a JAK1 inhibitor with effects on JAK2 3
Cytokine Signaling Affected
- JAK1 inhibition affects multiple cytokine signaling pathways involved in inflammatory diseases, including: 3, 4
- IL-6 signaling (via JAK1/JAK2)
- Type I and II interferons (IFNα/β/γ)
- IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 (via JAK1/JAK3)
- IL-10 family cytokines
Pharmacodynamic Effects
- In healthy volunteers, upadacitinib administration results in dose- and concentration-dependent inhibition of: 1
- IL-6 (JAK1/JAK2)-induced STAT3 phosphorylation
- IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation
- Maximal inhibition occurs 1 hour after dosing and returns to near baseline by the end of the dosing interval 1
Clinical Implications of Mechanism
- By inhibiting JAK1-mediated signaling, upadacitinib reduces the activity of multiple pro-inflammatory cytokines simultaneously, which explains its efficacy across various immune-mediated inflammatory diseases 3, 2
- This broad mechanism of action allows upadacitinib to be effective in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis, Crohn's disease, and ulcerative colitis 2, 3
- The selectivity for JAK1 over other JAK isoforms may contribute to its efficacy and safety profile compared to less selective JAK inhibitors 3, 2
Pharmacokinetic Considerations
- Upadacitinib plasma exposures are proportional to dose over the therapeutic range 1
- Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after once daily administration 1
- Pharmacokinetics are comparable across different inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, and axial spondyloarthritis 1, 5
Differences from Other JAK Inhibitors
- While all JAK inhibitors share the same basic mechanism of blocking cytokine signaling, they differ in their selectivity for specific JAK isoforms: 3, 4
- Tofacitinib: Preferentially inhibits JAK1, JAK3, and JAK2
- Baricitinib: Primarily inhibits JAK1 and JAK2
- Upadacitinib: Selectively inhibits JAK1 with effects on JAK2
- Filgotinib: Primarily inhibits JAK1
- The clinical relevance of these differences in JAK selectivity to therapeutic effectiveness is not currently fully established 1, 3
Understanding upadacitinib's mechanism as a selective JAK1 inhibitor helps explain its efficacy across multiple inflammatory conditions while providing insight into its potential safety profile and clinical applications.