Indications
Upadacitinib is prescribed for adult patients who suffer from moderately to severely active rheumatoid arthritis or active psoriatic arthritis and have shown an inadequate response or intolerance to one or more DMARDs, including TNF blockers. In Europe, it can be administered as a standalone treatment or combined with methotrexate for managing these conditions. Additionally, Upadacitinib is approved for patients aged 12 and older with refractory, moderate-to-severe atopic dermatitis that is inadequately controlled by other systemic therapies, or when such therapies are not advisable. For adult patients with active ankylosing spondylitis or radiographic axial spondyloarthritis who have not responded adequately to conventional therapy, and for those with non-radiographic axial spondyloarthritis exhibiting objective signs of inflammation who have had an inadequate response to TNF blockers, Upadacitinib is indicated. Furthermore, Upadacitinib is prescribed for adults with moderately to severely active ulcerative colitis or Crohn's disease who have not responded to or cannot tolerate either conventional therapies or biologic agents, including TNF blockers. It is important to note that combining Upadacitinib with other JAK inhibitors, biologic DMARDs, or powerful immunosuppressants is not recommended.
Pharmacodynamics
As a disease-modifying anti-rheumatic drug, Upadacitinib functions by inhibiting Janus Kinases (JAKs), which are crucial components in the signaling pathways of pro-inflammatory cytokines involved in autoimmune inflammatory conditions like rheumatoid arthritis. Clinical trials have shown that Upadacitinib reduces pro-inflammatory interleukins, temporarily increases lymphocyte levels, and results in minimal changes in immunoglobulin levels from baseline.
Absorption
Upadacitinib demonstrates a dose-proportional pharmacokinetic profile across its therapeutic dose range. Upon oral administration, the median time to reach maximum concentration (Tmax) is between 2 to 4 hours. Steady-state plasma concentrations are achieved within four days of consistent once-daily dosing, with negligible accumulation. Food intake does not significantly affect the area under the curve (AUC), maximum concentration (Cmax), or minimum concentration (Cmin) of Upadacitinib from the extended-release formulation.
Metabolism
Upadacitinib primarily undergoes metabolism via the enzyme CYP3A4, although it is considered a nonsensitive substrate for this enzyme. Additionally, it is metabolized to a lesser degree by CYP2D6. In human studies using radiolabeled Upadacitinib, approximately 79% of the total plasma radioactivity was attributed to the parent compound, while about 13% corresponded to the principal metabolite, which is produced first through mono-oxidation followed by glucuronidation. Notably, there are no identified active metabolites of Upadacitinib.
Mechanism of Action
Upadacitinib is a targeted therapy designed to inhibit the activity of Janus Kinase 1 (JAK1), a key player in the signaling pathways that drive rheumatoid arthritis (RA), a chronic autoimmune inflammatory disorder. This condition is characterized by the complex interactions of immune cells, particularly T- and B-lymphocytes, and the release of pro-inflammatory cytokines such as TNF, TGF, and IL-6. These cytokines rely on the Janus Kinase (JAK) family for signal transduction, which ultimately influences various immune-mediated processes. The JAK family, comprising four isoforms-JAK1, JAK2, JAK3, and Tyrosine Kinase 2-partners with intracellular domains of Type I/II cytokine receptors to activate downstream signaling. JAK1 specifically is involved in pathways activated by interleukins such as IL-6, which is pivotal for B- and T-cell differentiation and inflammatory response. Upon cytokine-receptor interaction, JAKs trigger the JAK-STAT pathway, leading to phosphorylation that activates STAT molecules. These activated STATs then migrate to the cell nucleus to initiate transcription of genes that propagate inflammatory responses, including immune cell proliferation and differentiation. Upadacitinib selectively inhibits JAK1, thereby disrupting these inflammatory processes with minimal impact on JAK3, thus offering a better safety profile. In cellular assays, Upadacitinib effectively reduces JAK1/3-induced phosphorylation of STAT3/5 mediated by IL-6/7, highlighting its therapeutic potential in managing RA.
