Tofacitinib

Mechanism

💊 Common Business Names

Xeljanz, Jakinil, Tofacin, Tofajak, Tofacit.

🔬 Pharmacological Group

Selective inhibitor of Janus kinases (mainly JAK1 and JAK3). oral tsDMARD.

Mechanism of Action

Unlike traditional biologic drugs that block the cytokine's soluble ligand, tofacitinib modulates intracellular receptor signaling:

• Selective and competitive inhibition of JAK1 and JAK3: Reversibly binds to the ATP coupling site in the kinase domains of JAK1 and JAK3 proteins, functionally blocking the mutual JAK-STAT signaling pathway. To a lesser extent it interferes with JAK2.
• Blocking the Transcription of Inflammatory Interleukins:
  1. Cytokine surface receptors lack intrinsic enzymatic activity. When its corresponding cytokine is coupled, phosphorylation mediated by JAK protein kinases occurs.
  2. Blocking JAK1/JAK3 prevents phosphorylation of STAT adapter proteins (signal transducers and activators of transcription).
  3. The dimerization and nuclear translocation of STAT is interrupted, quantitatively slowing down the gene transcription of fundamental proinflammatory cytokines such as IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21 and interferon gamma (IFN-γ). This drastically decreases the activation of T helper lymphocytes, neutrophils and synovial dural inflammation.

Pharmacokinetics

Key Pharmacokinetics

Indicators and dose

Dosage and Adjustment

• Adults (Rheumatoid Arthritis and Psoriatic Arthritis):
  • Immediate Release Tablets: 5 mg orally twice a day.
  • Extended Release Tablets: 11 mg orally once a day.
• Adults (Moderate-Severe Ulcerative Colitis):
  • Induction Phase: 10 mg orally twice daily for a minimum of 8 to 16 weeks.
  • Maintenance Phase: 5 mg orally twice a day.
• Pediatrics: Not routinely established for children under 18 years of age. Only approved for use in polyarticular juvenile idiopathic arthritis in children over 2 years of age in specific oral formulation and doses adjusted to body weight.
• Adjustment in Kidney Failure:
  • Cl_cr ≥ 30 mL/min: No adjustment required for standard doses.
  • Cl_cr < 30 mL/min: Reduce the dose to a maximum of 5 mg once a day (or half the corresponding standard dose).
• Adjustment in Liver Failure:
  • Moderate Liver Failure (Child-Pugh B): Reduce the weekly or daily dose by half (maximum of 5 mg once a day).
  • Severe Liver Failure (Child-Pugh C): Absolutely contraindicated.

Security

Contraindications

• Absolute: Severe liver failure (Child-Pugh C); severe chronic active infections or localized bacteremia; active tuberculosis; absolute lymphocyte count less than 500 cells/µL; absolute neutrophil count less than 1000 cells/µL; basal hemoglobin levels less than 9 g/dL; personal history or high risk of venous or arterial thromboembolism (VTE); pregnancy and active breastfeeding period.
• Relative: Cumulative cardiovascular risk factors; history of chronic diverticulitis (associated with a minor increase in gastrointestinal perforations).

Adverse Effects (ADR)

• Common / Mild: Transient headache, nausea, dyspepsia, mild diarrhea, upper respiratory tract infections, nasopharyngitis, increase in serum lipid levels (total cholesterol, LDL, HDL), transient elevation of creatine kinase (CK).
• Rare / Serious: Reactivation of the Herpes Zoster virus (reactivation rate significantly higher than that of classic biologics); Deep venous thromboembolism and pulmonary embolism (with high doses of 10 mg twice a day); lymphopenia and neutropenia; reactivation of latent tuberculosis; gastrointestinal perforations of local inflammatory origin.

Safety Alert: Risk of Venous Thromboembolism (VTE)

Following the safety results of the "ORAL Surveillance" post-marketing clinical trial, the FDA and EMA have issued critical use alerts: tofacitinib dose-dependently increases the risk of deep vein thrombosis (DVT), pulmonary embolism (PE) and major cardiovascular events (MACE) in patients with rheumatoid arthritis over 50 years of age who have at least one cardiovascular risk factor. The use of tofacitinib as a first-line therapeutic is prohibited and is limited to patients without viable treatment options or refractory to anti-TNF agents.

Drug Interactions

• Potent CYP3A4 inhibitors (Ketoconazole, Itraconazole, Fluconazole, Clarithromycin): They decrease the clearance of tofacitinib, significantly increasing its serum plasma concentrations. The recommended dose of tofacitinib should be reduced by half (50%) when coadministered with potent CYP3A4 inhibitors.
• Potent CYP3A4 inducers (Rifampin, Carbamazepine, Phenytoin): They dramatically accelerate the clearance of tofacitinib, reducing its clinical efficacy to undetectable therapeutic levels. Coadministration not recommended.
• Live Attenuated Virus Vaccines: Contraindicated simultaneously.

Pregnancy and Breastfeeding

Absolutely not recommended; Preliminary data in animal models indicate the existence of dose-dependent teratogenic effects associated with fetal skeletal defects. Taking contraceptives should be guaranteed during therapy and until at least 1-2 months after stopping treatment. Breastfeeding: Contraindicated; Its exact excretion rate is unknown, but due to the short half-life and powerful biological effect, it is preferred to suspend treatment so as not to compromise the infant's hematopoiesis.