Tofacitinib

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Tofacitinib
Tofacitinib.svg
Clinical data
Trade names Xeljanz, Jaquinus, Tofacinix, Others
Other namesCP-690550
AHFS/Drugs.com Monograph
MedlinePlus a613025
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Janus kinase (JAK) inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Liver (via CYP3A4 and CYP2C19)
Elimination half-life 3 hours
Excretion Urine
Identifiers
  • 3-[(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
CAS Number
PubChem CID
PubChemSID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.215.928 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H20N6O
Molar mass 312.377 g·mol−1
3D model (JSmol)
  • CC1CCN(C(=O)CC#N)CC1N(C)c1ncnc2[nH]ccc12
  • InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1
  • Key:UJLAWZDWDVHWOW-YPMHNXCESA-N

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. [8] [9] [10] It is a janus kinase (JAK) inhibitor, [8] [9] discovered and developed by the National Institutes of Health and Pfizer.

Contents

Common side effects include diarrhea, headache, and high blood pressure. [10] Serious side effects may include infections, cancer, and pulmonary embolism. [10] [11] In 2019, the safety committee of the European Medicines Agency began a review of tofacitinib and recommended that doctors temporarily not prescribe the 10 mg twice-daily dose to people at high risk for pulmonary embolism. [12] The U.S. Food and Drug Administration (FDA) also released warnings about the risk of blood clots. [13] [14] [15] An important side effect of Jakinibs is serious bacterial, mycobacterial, fungal and viral infections. In the phase III trials of tofacitinib among opportunistic infections, pulmonary tuberculosis (TB) was reported in 3 cases all of which were initially negative upon screening for TB. [16]

It was approved for medical use in the United States in November 2012. [17] The extended release version was approved in February 2016. [18] It is available as a generic medication. [19]

Medical uses

Rheumatoid arthritis

Tofacitinib citrate is approved for medical use in the United States with an indication "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate." [20] [8]

In the European Union, in combination with methotrexate, tofacitinib citrate is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. [9] It can be given as monotherapy in case of intolerance to methotrexate or when treatment with MTX is inappropriate. [9]

Ulcerative colitis

In May 2018, the FDA approved tofacitinib citrate "for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis." [21] Tofacitinib citrate is the first oral JAK inhibitor approved for use in chronic ulcerative colitis.

Adverse effects

Tofacitinib was initially not approved by European regulatory agencies because of concerns over efficacy and safety, [22] although by 2018, the European Commission had approved it. [23] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility. [8]

The most commonly reported adverse reactions during the first three months in controlled clinical trials (occurring in 2% or more of patients treated with tofacitinib citrate monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, diarrhea, and nasopharyngitis (the "common cold"). [8]

Tofacitinib is required by the 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. [20] 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 who 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, but 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. [8]

According to postmarketing research, tofacitinib may also increase the risk for pulmonary embolism. Prescribers should consider risk factors for pulmonary embolism, including age, obesity, smoking, and immobilization before prescribing this medication. Patients taking this medication, irrespective of indication or risk factors, should be monitored for signs and symptoms of pulmonary embolism. [24]

Mechanism

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. [25]

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 JAK3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3. [26]

History

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). [27] In 1994, Pfizer was approached by the NIH to form a public-private partnership to evaluate and bring to market experimental compounds based on this research. [27] 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." [27] 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. [28]

The drug was coded as CP-690,550 [29] during development. Its original recommended International nonproprietary name (rINN) was tasocitinib, [30] but that was overruled during the INN approval process as being not optimally differentiable from other existing INNs, so the name "tofacitinib" was proposed and became the INN.

In November 2012, the FDA approved tofacitinib for treatment of rheumatoid arthritis. [8] [17]

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. [31]

In November 2012, the 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. [20] The FDA approved only the five-mg, twice-daily dose on the grounds that a higher dose was not considered to have an adequate risk-to-benefit ratio. [32]

In September 2020, the FDA approved tofacitinib for the treatment of children and adolescents two years of age and older with active polyarticular course juvenile idiopathic arthritis. [33]

In December 2021, the FDA approved tofacitinib for the treatment of adults with active ankylosing spondylitis. [34]

As of June 2021, tofacitinib is available as a generic medicine in the US. [35] [36]

Society and culture

Names

Tofacitinib is marketed as Xeljanz except for Russia, where it is marketed as Jaquinus. [37]

Research

As of August 2024, recent research on tofacitinib confirms its effectiveness in treating moderate to severe rheumatoid arthritis and other inflammatory conditions. New studies are exploring its safety profile, expanding indications (such as ankylosing spondylitis and atopic dermatitis), and comparing it with other treatments. Ongoing research also focuses on optimizing dosage and evaluating combination therapies. For the latest findings, consult recent peer-reviewed studies and clinical guidelines. [38]

It has demonstrated effectiveness in the treatment of psoriasis in phase III studies. As of November 2013 it was studied in immunological diseases, as well as for the prevention of organ transplant rejection. [39] [40] [41] [42]

Psoriasis

Tofacitinib is an investigational drug in psoriasis. As of October 2015, it demonstrated its effectiveness for plaque psoriasis in phase III, randomized, controlled trials in comparison to placebo and to etanercept. [32] [43] [44] [45] In particular, a ten-mg, twice-daily dose of tofacitinib was shown to be not inferior to etanercept 50 mg, subcutaneously, twice weekly. [44] In October 2015, the FDA rejected approval of tofacitinib for the treatment of psoriasis due to safety concerns. [46]

Alopecia areata

Based on preclinical studies in a mouse model of the disease, [47] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports [48] [49] suggested potential efficacy, as did a phase II open-label clinical trial, [50] published in tandem with a phase II clinical trial showing the same for ruxolitinib. [51]

Vitiligo

In a June 2015 case report, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months. [52]

Atopic dermatitis

The results of using tofacitinib in six patients with recalcitrant atopic dermatitis was published in September 2015. All saw improvement in their atopic dermatitis without any adverse events. [53]

Ankylosing spondylitis

In 2021 and 2022, results of a phase III randomised, double-blind, placebo-controlled trial were reported, that showed significant improvements for patients with active ankylosing spondylitis compared to placebo. [54] [55]

Ulcerative colitis

As of November 2013, it was studied for treatment of inflammatory bowel disease. [56] [45] The FDA approved tofacitinib in May 2018 for treatment of ulcerative colitis. [21]

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

<span class="mw-page-title-main">Ulcerative colitis</span> Inflammatory bowel disease that causes ulcers in the colon

Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autoimmune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory medication

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (TNFα) is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

<span class="mw-page-title-main">Certolizumab pegol</span> Pharmaceutical drug

Certolizumab pegol, sold under the brand name Cimzia, is a biopharmaceutical medication for the treatment of Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha (TNF-α) and is manufactured by UCB.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

<span class="mw-page-title-main">Golimumab</span> Pharmaceutical drug

Golimumab, sold under the brand name Simponi, is a human monoclonal antibody which is used as an immunosuppressive medication. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory molecule and hence is a TNF inhibitor. Profound reduction in C-reactive protein (CRP) levels, interleukin (IL)-6, intercellaular adhesion molecules (ICAM)-1, matrix metalloproteinase (MMP)-3, and vascular endothelial growth factor (VEGF) demonstrates golimumab as an effective modulator of inflammatory markers and bone metabolism. Golimumab is given via subcutaneous injection.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

Ixekizumab, sold under the brand name Taltz, is an injectable medication for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody. The substance acts by binding interleukin 17A and neutralizing it, reducing inflammation.

<span class="mw-page-title-main">Secukinumab</span> Monoclonal antibody against IL-17

Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.

<span class="mw-page-title-main">Baricitinib</span> Chemical compound

Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.

<span class="mw-page-title-main">Filgotinib</span> Chemical compound

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

Risankizumab, sold under the brand name Skyrizi, is a humanized monoclonal antibody used for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. It is designed to target interleukin 23A (IL-23A). It is given by subcutaneous injection.

<span class="mw-page-title-main">Upadacitinib</span> Biopharmaceutical drug

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">Janus kinase 3 inhibitor</span>

Janus kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus kinase 3. They are used for the treatment of autoimmune diseases. The Janus kinases are a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3, and TYK2. They signal via the JAK/STAT pathway, which is important in regulating the immune system. Expression of JAK3 is largely restricted to lymphocytes, while the others are ubiquitously expressed, so selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases.

References

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  42. ↑ Kalluri HV, Hardinger KL (August 2012). "Current state of renal transplant immunosuppression: Present and future". World Journal of Transplantation. 2 (4): 51–68. doi: 10.5500/WJT.v2.i4.51 . PMC   3782235 . PMID   24175197.
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