Indications
Tofacitinib is prescribed for adult patients dealing with moderately-to-severely active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis, particularly when there is an inadequate response to or intolerance of one or more TNF blockers. Additionally, it is available as an oral solution for patients aged two years and older for the treatment of polyarticular course juvenile idiopathic arthritis under similar circumstances. The use of Tofacitinib in combination with other biologic disease-modifying anti-rheumatic drugs or potent immunosuppressive agents like azathioprine or cyclosporine is not recommended.
Pharmacodynamics
Tofacitinib operates by targeting the inflammation associated with rheumatoid arthritis through inhibition of janus kinases, which are integral to the inflammatory response. In placebo-controlled trials involving rheumatoid arthritis patients, those administered 5 mg or 10 mg doses of tofacitinib twice daily demonstrated higher ACR20 response rates within two weeks. The ACR20 is defined as at least a 20% reduction in joint pain or tenderness and a 20% reduction in arthritis-related pain and other parameters as outlined by the American College of Rheumatology response criteria. Benefits such as improved physical functioning were notably greater than those observed with the placebo. Common adverse effects include headaches, diarrhea, nausea, nasopharyngitis, and upper respiratory tract infections, with additional serious risks including immunologic and hematological complications like lymphopenia, neutropenia, anemia, and an elevated risk of cancer and infection. Patients should be screened for latent tuberculosis infections prior to starting treatment and monitored consistently for signs of any infections during therapy. Treatment should be avoided in patients with active systemic or localized infections and must be halted if serious infections arise. Tofacitinib is linked with increased risks of certain lymphomas and malignancies. Regular monitoring of lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids is recommended.
Absorption
Tofacitinib demonstrates an oral absorption rate of 74% with absolute bioavailability, achieving peak plasma concentrations (T_max) typically between 0.5 to 1 hour after administration. Consuming high-fat meals does not affect the area under the curve (AUC) but can reduce the maximum plasma concentration (C_max) by 32%.
Metabolism
The metabolism of Tofacitinib occurs in the liver, primarily involving the cytochrome P450 enzymes CYP3A4 and CYP2C19. The metabolites produced during this process are inactive.
Mechanism of Action
Tofacitinib functions as a selective and reversible inhibitor of the Janus kinase (JAK) pathways, which are crucial in mediating cytokine signaling associated with the pathogenesis of autoimmune disorders, such as rheumatoid arthritis. This condition is marked by dysregulated pro-inflammatory cytokines, including IL-7, IL-15, IL-21, IL-6, IFN-alpha, and IFN-beta, leading to tissue inflammation and joint damage. By targeting JAKs, tofacitinib effectively disrupts the phosphorylation and activation of STATs, key proteins in the JAK-STAT signaling cascade. This pathway plays a significant role in regulating hematopoiesis and immune cell functions. Consequently, tofacitinib attenuates the inflammatory response, providing therapeutic benefits in managing rheumatoid arthritis. There is also emerging evidence suggesting that tofacitinib may exert its efficacy through additional mechanisms beyond JAK-STAT inhibition.
