|Trade names||Xeljanz, Jakvinus, Others|
|By mouth (tablets)|
|Metabolism||Liver (via CYP3A4 and CYP2C19)|
|Elimination half-life||3 hours|
|Chemical and physical data|
|Molar mass||312.369 g/mol g·mol−1|
|3D model (JSmol)|
Common side effects include diarrhea, headache, and high blood pressure. Serious side effects may include infections, cancer, and pulmonary embolism. It is in the janus kinase (JAK) inhibitor class, discovered and developed by the National Institutes of Health and Pfizer.
In November 2012, the U.S. FDA approved tofacitinib citrate "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate." It was later approved in Japan, Switzerland and others (but not the EU). It is marketed as Xeljanz in all regions except for Russia where it will be marketed as Jakvinus or Jaquinus.
In May 2018, the U.S. FDA approved tofacitinib citrate "for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis." Tofacitinib citrate is the first oral JAK inhibitor approved for chronic use in ulcerative colitis (tofacitinib is a small molecule, not a biologic).
Tofacitinib was not approved by European regulatory agencies because of concerns over efficacy and safety. Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.
The most commonly reported adverse reactions during the first three months in controlled clinical trials (occurring in greater than or equal to 2% of patients treated with tofacitinib citrate monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, diarrhea, and nasopharyngitis (the "common cold").
Tofacitinib is required by US FDA to have a boxed warning on its label about possible injury and death due to problems such as infections, Lymphoma and other malignancies which can arise from use of this drug. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving tofacitinib. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib while on immunosuppressive medications. Patients are warned to avoid use of tofacitinib citrate during an "active serious infection, including localized infections." Doctors are advised to use it with caution in patients that may be at increased risk of gastrointestinal perforations. Laboratory monitoring is recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. Tofacitinib claims to have no contraindications, however doctors are advised to reduce the patient's dosage when combined with "potent inhibitors of Cytochrome P450 3A4 (CYP3A4)," such as ketoconazole), or one or more combined medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 such as fluconazole. Furthermore, immunizations with live vaccines should be avoided by tofacitinib users.
It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.
In a mouse model of established arthritis, tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.
The potential significance of JAK3 inhibition was first discovered in the laboratory of John O'Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH). In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research. Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the "health and safety needs of the public." Pfizer worked with O'Shea's laboratory to define the structure and function of JAK3 and its receptors, and then handled the drug discovery, preclinical development, and clinical development of tofacitinib in-house.
The drug was coded as CP-690,550 during development. Its original recommended INN (rINN) was tasocitinib, but that was overruled during the INN approval process as being inoptimally differentiable from other existing INNs, so the name tofacitinib was proposed and became the INN.
In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Two rheumatologists interviewed by the magazine Nature Biotechnology complained that they were "shocked" and "disappointed" at the $2,055 a month wholesale price.
A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.
In November 2012, the U.S. FDA approved tofacitinib "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate." FDA approved only the 5 mg twice-daily dose on the grounds that a higher dose was not considered to have an adequate risk-to-benefit ratio.
It has demonstrated effectiveness in the treatment of psoriasis in Phase 3 studies. It is being studied for treatment of inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.
Tofacitinib is a current investigational drug in psoriasis. Tofacitinib has demonstrated its effectiveness for plaque psoriasis in Phase 3 randomized, controlled trials in comparison to placebo and to etanercept. In particular, a 10 mg twice-daily dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly.
Based on preclinical studies in a mouse model of the disease, tofacitinib has been investigated for the treatment of alopecia areata. Early case reports suggested potential efficacy, as did a phase II open-label clinical trial, published in tandem with a phase II clinical trial showing the same for ruxolitinib.
The results of using tofacitinib in 6 patients with recalcitrant atopic dermatitis was published in the September 2015. All saw improvement in their atopic dermatitis without any adverse events.
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- AS: Is Tofacitinib the Next Big Thing? Nov 2016