What is the mechanism of action of Rinvoq (upadacitinib)?

Mechanism of Action of Rinvoq (Upadacitinib)

Upadacitinib is a selective Janus kinase 1 (JAK1) inhibitor that works by blocking the JAK-STAT intracellular signal transduction pathway, preventing the phosphorylation and activation of STATs, thereby modulating the signaling of multiple inflammatory cytokines.

Detailed Mechanism

Upadacitinib functions through the following mechanisms:

• JAK Enzyme Inhibition:

  • Preferentially targets JAK1 with greater inhibitory potency compared to JAK2, JAK3, and TYK2 1
  • In cell-free isolated enzyme assays, upadacitinib shows greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2 1
  • In human leukocyte cellular assays, it more potently inhibits cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 than JAK2/JAK2 mediated STAT phosphorylation 1

• Cytokine Signaling Disruption:

  • Blocks signaling of multiple inflammatory cytokines that rely on the JAK-STAT pathway 2
  • Inhibits phosphorylation of downstream effector proteins 3
  • Specifically reduces immunopathogenic gene expression induced by type 1 interferons (IFNα/IFNβ) 2

• Pharmacodynamic Effects:

  • Causes dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood 1
  • Maximum inhibition occurs approximately 1 hour after dosing and returns to near baseline by the end of the dosing interval 1

Clinical Applications

Upadacitinib has been approved for several inflammatory conditions due to its selective JAK1 inhibition:

• Rheumatoid Arthritis: Standard of care for refractory RA 2
• Atopic Dermatitis: Approved for moderate-to-severe cases 2
• Psoriatic Arthritis: Demonstrated efficacy in clinical trials 4
• Inflammatory Bowel Disease: Shown efficacy in ulcerative colitis and Crohn's disease 2
• Ankylosing Spondylitis: Effective for signs and symptoms in patients with active disease 2

Pharmacokinetic Properties

• Achieves steady-state plasma concentrations within 4 days with minimal accumulation after once-daily administration 1
• Demonstrates dose-proportional plasma exposures across the therapeutic dose range 1
• Shows comparable pharmacokinetics across different inflammatory conditions including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, and ankylosing spondylitis 1

Differences from Other JAK Inhibitors

• While other JAK inhibitors like baricitinib target both JAK1 and JAK2, upadacitinib is engineered to be more selective for JAK1 2, 5
• This selectivity may contribute to its efficacy profile in certain conditions while potentially affecting its safety profile 2
• In atopic dermatitis, higher doses of upadacitinib (30 mg daily) demonstrate higher efficacy at reducing EASI scores compared to baricitinib 2, 5

Safety Considerations

• Like other JAK inhibitors, upadacitinib carries FDA warnings about increased risk of serious infections, particularly herpes zoster, cardiovascular events, malignancy, and thrombosis 2
• Appropriate laboratory monitoring is recommended before and during treatment 2

Understanding upadacitinib's selective JAK1 inhibition mechanism helps explain its efficacy across multiple inflammatory conditions while providing context for its safety profile and clinical applications.