Tofacitinib

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis.[2][3]

Tofacitinib
Clinical data
Trade namesXeljanz, Jakvinus, Tofacinix, Others
Other namesCP-690550
AHFS/Drugs.comMonograph
MedlinePlusa613025
License data
Pregnancy
category
  • AU: D [1]
  • US: N (Not classified yet) [1]
    Routes of
    administration    		By mouth (tablets)
    Drug classJanus kinase (JAK) inhibitor
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability74%
    Protein binding40%
    MetabolismLiver (via CYP3A4 and CYP2C19)
    Elimination half-life3 hours
    ExcretionUrine
    Identifiers
    CAS Number
    PubChem CID
    PubChem SID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.215.928
    Chemical and physical data
    FormulaC16H20N6O
    Molar mass312.377 g·mol−1
    3D model (JSmol)

    Common side effects include diarrhea, headache, and high blood pressure.[2] Serious side effects may include infections, cancer, and pulmonary embolism.[2][4] In 2019, the safety committee of the European Medicines Agency (EMA) 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.[5] The U.S. Food and Drug Administration (FDA) also released warnings about the risk of blood clots.[6][7][8]

    It is in the janus kinase (JAK) inhibitor class, discovered and developed by the National Institutes of Health and Pfizer.

    Medical uses

    Rheumatoid arthritis

    In November 2012, the U.S. Food and Drug Administration (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."[9] 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.[10]

    Ulcerative colitis

    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."[3] Tofacitinib citrate is the first oral JAK inhibitor approved for chronic use in ulcerative colitis (tofacitinib is a small molecule, not a biologic).

    Adverse effects

    Tofacitinib was initially not approved by European regulatory agencies because of concerns over efficacy and safety,[11] although by 2018 the European Commission had approved it.[12] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[13]

    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").[13]

    Tofacitinib is required by the U.S. Food and Drug Administration (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.[9] 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.[13]

    According to post-marketing research, tofacitinib may also increase the risk for pulmonary embolism. Prescribers should consider risk factors for pulmonary embolism before prescribing this medication. Risk factors include age, obesity, smoking and immobilization. Patients taking this medication, irrespective of indication or risk factors, should be monitored for signs and symptoms of pulmonary embolism.[14]

    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.[15]

    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.[16]

    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).[17] 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.[17] 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."[17] 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.[18]

    The drug was coded as CP-690,550[19] during development. Its original recommended INN (rINN) was tasocitinib,[20] 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.[18]

    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.[21]

    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.[9] The 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.[22]

    Research

    It has demonstrated effectiveness in the treatment of psoriasis in Phase 3 studies. It is being studied for treatment of inflammatory bowel disease,[23][24] and other immunological diseases, as well as for the prevention of organ transplant rejection.[25][26][27][28]

    Psoriasis

    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.[22][29][30] In particular, a 10 mg twice-daily dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly.[30] Approval of tofacitinib for the treatment of psoriasis was rejected by the FDA due to safety concerns.[31]

    Alopecia areata

    Based on preclinical studies in a mouse model of the disease,[32] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports[33][34] suggested potential efficacy, as did a phase II open-label clinical trial,[35] published in tandem with a phase II clinical trial showing the same for ruxolitinib.[36]

    Vitiligo

    In a June 2015 case report, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[37]

    Atopic dermatitis

    The results of using tofacitinib in six patients with recalcitrant atopic dermatitis was published in the September 2015. All saw improvement in their atopic dermatitis without any adverse events.[38]

    Ankylosing spondylitis

    As of 2016 it is undergoing a phase II trial for ankylosing spondylitis.[39]

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    References
    1. Use During Pregnancy and Breastfeeding
    2. "Tofacitinib Citrate". The American Society of Health-System Pharmacists. Retrieved 1 June 2018.
    3. "FDA approves new treatment for moderately to severely active ulcerative colitis". U.S. Food and Drug Administration (FDA) (Press release). 30 May 2018. Archived from the original on 15 December 2019. Retrieved 1 June 2018. This article incorporates text from this source, which is in the public domain.
    4. "Safety Alerts for Human Medical Products - Xeljanz, Xeljanz XR (tofacitinib): Safety Communication - Safety Trial Finds Increased Risk of Blood Clots in the Lungs and Death with Higher Dose in Rheumatoid Arthritis Patients". U.S. Food and Drug Administration (FDA). Retrieved 2 March 2019. This article incorporates text from this source, which is in the public domain.
    5. "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 13-16 May 2019, May 17, 2019". European Medicines Agency (EMA). Retrieved 17 May 2019.
    6. "Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose". U.S. Food and Drug Administration (FDA). 26 July 2019. Archived from the original on 15 December 2019. Retrieved 10 August 2019. This article incorporates text from this source, which is in the public domain.
    7. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). U.S. Food and Drug Administration (FDA) (Podcast). 5 August 2019. Retrieved 15 December 2019.
    8. "FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR)". U.S. Food and Drug Administration. 15 December 2019. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
    9. "FDA approves Xeljanz for rheumatoid arthritis". U.S. Food and Drug Administration (FDA) (Press release). 6 November 2012. Archived from the original on 2 April 2014.
    10. Pfizer Provides Update on Global Regulatory Approvals and Launches of XELJANZ® (tofacitinib citrate) for the Treatment of Rheumatoid Arthritis. July 2013
    11. Nordqvist C (27 April 2013). "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. Retrieved 2 August 2013.
    12. McKee S (29 June 2018). "EU approves Pfizer's Xeljanz for psoriatic arthritis". PharmaTimes. Retrieved 3 June 2019.
    13. "XELJANZ- tofacitinib tablet, film coated / XELJANZ XR- tofacitinib tablet, film coated, extended release". DailyMed. 30 August 2019.
    14. FDA Warns of Risk for PE, Death With Higher Dose Tofacitinib (Xeljanz) for RA - Medscape - Feb 25, 2019.
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    30. Bachelez H, van de Kerkhof PC, Strohal R, Kubanov A, Valenzuela F, Lee JH, et al. (August 2015). "Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial". Lancet. 386 (9993): 552–61. doi:10.1016/S0140-6736(14)62113-9. PMID 26051365.
    31. "Pfizer Receives Complete Response Letter from FDA for Oral XELJANZ® (tofacitinib citrate) Supplemental New Drug Application for Moderate to Severe Chronic Plaque Psoriasis" (Press release). Pfizer. 14 October 2015.
    32. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. (September 2014). "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition". Nature Medicine. 20 (9): 1043–9. doi:10.1038/nm.3645. PMC 4362521. PMID 25129481.
    33. Craiglow BG, King BA (December 2014). "Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis". The Journal of Investigative Dermatology. 134 (12): 2988–2990. doi:10.1038/jid.2014.260. PMID 24940651.
    34. Jabbari A, Nguyen N, Cerise JE, Ulerio G, de Jong A, Clynes R, et al. (August 2016). "Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers". Experimental Dermatology. 25 (8): 642–3. doi:10.1111/exd.13060. PMC 4963264. PMID 27119625.
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    36. Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al. (September 2016). "Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata". JCI Insight. 1 (15): e89790. doi:10.1172/jci.insight.89790. PMC 5033756. PMID 27699253.
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    38. Levy LL, Urban J, King BA (September 2015). "Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate". Journal of the American Academy of Dermatology. 73 (3): 395–9. doi:10.1016/j.jaad.2015.06.045. PMID 26194706.
    39. AS: Is Tofacitinib the Next Big Thing? Nov 2016
    • "Tofacitinib". Drug Information Portal. U.S. National Library of Medicine.
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