XELTIN

Indications

• Moderate to severe rheumatoid arthritis
• Psoriatic arthritis
• Moderate to severe ulcerative colitis
• Ankylosing spondylitis

Dosage

Adults: For rheumatoid arthritis: 5 mg twice daily or 11 mg once daily using modified-release tablets. For ulcerative colitis and other indications, consult specific product literature for guidelines.

Mechanism of action

Tofacitinib acts as a partial and reversible inhibitor of Janus kinases (JAKs), which are critical enzymes in the signaling pathways of pro-inflammatory cytokines. By inhibiting JAKs, it prevents the phosphorylation and activation of signal transducers and activators of transcription (STATs), reducing the transcription of genes involved in inflammation and immune response. This modulation of the JAK-STAT signaling pathway decreases tissue inflammation and joint damage in conditions such as rheumatoid arthritis.

Pharmacodynamics

Clinical trials have shown that tofacitinib effectively targets inflammation in rheumatoid arthritis, with significant improvements in ACR20 responses (20% reduction in joint pain and other measures of arthritis) observed within 2 weeks in some patients. Common adverse effects include headaches, diarrhea, nausea, and upper respiratory infections, while more serious effects can include lymphopenia, neutropenia, anemia, and an increased risk of infections and cancers. Close monitoring for infections, especially tuberculosis, is essential during treatment.

Pharmacokinetics

Tofacitinib is absorbed after oral administration, with peak plasma concentrations typically reached within 1-2 hours. It is primarily metabolized by CYP3A4 enzymes, with a half-life of approximately 3 hours. The drug's exposure can be affected by co-administration with other medications that induce or inhibit CYP enzymes, necessitating careful consideration of drug interactions. Renal impairment can also affect dosing, and caution is advised in patients with moderate to severe renal conditions.

Contra-indications

• Severe hypersensitivity to tofacitinib or any of its excipients
• Severe renal impairment (end-stage renal disease)
• Active infections, including tuberculosis
• History of malignancy, particularly non-melanoma skin cancer

Adverse effects

• Headache
• Diarrhea
• Nausea
• Nasopharyngitis
• Upper respiratory tract infection
• Lymphopenia
• Neutropenia
• Anemia
• Increased risk of serious infections
• Increased risk of malignancies

Interactions

• Ciclosporin: Severe (increases exposure)
• Filgotinib: Severe (increases risk of immunosuppression)
• Tacrolimus: Severe (increases exposure)
• Fluconazole: Unknown (increases exposure)
• Cobicistat: Unknown (increases exposure)
• Dabrafenib: Unknown (decreases exposure)
• Bosentan: Unknown (decreases exposure)
• Idelalisib: Unknown (increases exposure)
• Clarithromycin: Unknown (increases exposure)
• Mitotane: Unknown (decreases exposure)

Precautions

• Screen for tuberculosis and viral hepatitis before treatment
• Monitor for signs of infection during treatment
• Monitor for haematological abnormalities before and during treatment
• Periodic skin examination recommended for patients at increased risk for skin cancer
• Caution in moderate to severe renal impairment

Pregnancy

Avoid due to toxicity observed in animal studies.

Breast-feeding

Avoid; no information available.

Storage

Store at room temperature, away from moisture and light.

Formulations

• 100 mg film-coated tablets
• 200 mg film-coated tablets

Mechanism of action

Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. Tofacitinib citrate, a Janus kinase (JAK) inhibitor, is an immunomodulating agent and a disease-modifying antirheumatic drug (DMARD). JAKs are intracellular enzymes that mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. Tofacitinib inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK2/JAK2). In vitro, tofacitinib inhibited the activity of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 (concentration that inhibits activity by 50%) values of 406, 56, and 1377 nM, respectively. The relevance of specific JAK combinations to the therapeutic efficacy of tofacitinib is not known. /Tofacitinib citrate/ Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-beta. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.

Pharmacodynamics

Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.