Tofacitinib

Tofacitinib
Names
Trade namesXeljanz, Jaquinus, Tofacinix, Others
Other namesCP-690550
IUPAC name
  • 3-[(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Drug classJanus kinase (JAK) inhibitor and disease-modifying antirheumatic drug (DMARD)[1]
Main usesRheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ulcerative colitis[1]
Side effectsDiarrhea, headache, infections, cancer, pulmonary embolism[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D[2]
  • US: N (Not classified yet)[2]
    Routes of
    use    		By mouth (tablets)
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa613025
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [3][4]
    • US: ℞-only [5]
    • EU: Rx-only [6]
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability74%
    Protein binding40%
    MetabolismLiver (via CYP3A4 and CYP2C19)
    Elimination half-life3 hours
    ExcretionUrine
    Chemical and physical data
    FormulaC16H20N6O
    Molar mass312.377 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1CCN(CC1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N
    InChI
    • 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, juvenile idiopathic arthritis, and ulcerative colitis.[1] It is used when other treatments are not effective.[6] It is taken by mouth.[1]

    Common side effects include diarrhea, headache, and high blood pressure.[1] Serious side effects may include infections, cancer, angioedema, and pulmonary embolism.[1] There are concerns that higher doses may increase the risk of death.[1] Use in pregnancy may harm the baby.[7] It is a janus kinase (JAK) inhibitor.[1]

    Tofacitinib was approved for medical use in the United States in 2012 and Europe in 2017.[1][6] In the United Kingdom it costs the NHS about £690 for 4 weeks of treatment at 5 mg twice per day as of 2021.[8] This amount in the United States costs about 4,600 USD.[9]

    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."[10][5]

    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.[6] It can be given as monotherapy in case of intolerance to methotrexate or when treatment with MTX is inappropriate.[6]

    Ulcerative colitis

    In 2018 it was approved in the US for adults with moderately to severely active ulcerative colitis.[11] Tofacitinib citrate is the first oral JAK inhibitor approved for chronic use in ulcerative colitis.

    Dosage

    It is usually taken at a dose of 5 mg twice per day, though in certain cases 10 mg twice per day may be used.[6]

    Side effects

    Tofacitinib was initially not approved by European regulatory agencies because of concerns over efficacy and safety,[12] although by 2018, the European Commission had approved it.[13] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[5]

    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").[5]

    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.[10] 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.[5]

    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.[14] The U.S. Food and Drug Administration (FDA) also released warnings about the risk of blood clots.[15][16][17]An important side effect of Jakinibs is serious bacterial, mycobacterial, fungal and viral infections. In the phase 3 trials of tofacitinib among opportunistic infections, pulmonary tuberculosis (TB) was reported in 3 cases all of which were initially negative upon screening for TB.[18]

    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.[19]

    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.[20]

    Tofacitinib is a small molecule, not a biologic.[21]

    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.[22]

    History

    It was discovered and developed by the National Institutes of Health and Pfizer.

    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).[23] 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.[23] 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."[23] 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.[24]

    The drug was coded as CP-690,550[25] during development. Its original recommended INN (rINN) was tasocitinib,[26] 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. Two rheumatologists interviewed by the magazine Nature Biotechnology complained that they were "shocked" and "disappointed" at the $2,055 a month wholesale price.[24]

    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.[27]

    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.[10] 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.[28]

    Society and culture

    Names

    Tofacitinib is marketed as Xeljanz except for Russia, where it is marketed as Jaquinus.[29]

    Research

    It has been studied for treatment of inflammatory bowel disease,[30][31] and other immunological diseases, as well as for the prevention of organ transplant rejection.[32][33][34][35]

    Psoriasis

    Tofacitinib is an investigational drug in psoriasis. It demonstrated its effectiveness for plaque psoriasis in phase III, randomized, controlled trials in comparison to placebo and to etanercept.[28][36][37] In particular, a ten-mg, twice-daily dose of tofacitinib was shown to be not inferior to etanercept 50 mg, subcutaneously, twice weekly.[37] Approval of tofacitinib for the treatment of psoriasis was rejected by the FDA due to safety concerns.[38]

    Alopecia areata

    Based on preclinical studies in a mouse model of the disease,[39] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports[40][41] suggested potential efficacy, as did a phase II open-label clinical trial,[42] published in tandem with a phase II clinical trial showing the same for ruxolitinib.[43]

    References

    1. 1 2 3 4 5 6 7 8 9 10 "Tofacitinib Monograph for Professionals". Drugs.com. Archived from the original on 28 September 2021. Retrieved 5 October 2021.
    2. 1 2 "Tofacitinib Use During Pregnancy". Drugs.com. 15 April 2020. Archived from the original on 29 November 2020. Retrieved 23 October 2020.
    3. ↑ "10 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 13 October 2020. Archived from the original on 27 July 2019. Retrieved 3 November 2020.
    4. ↑ "Xeljanz 11 mg prolonged release tablets - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 9 August 2020. Retrieved 3 November 2020.
    5. 1 2 3 4 5 "Xeljanz- tofacitinib tablet, film coated Xeljanz XR- tofacitinib tablet, film coated, extended release Xeljanz- tofacitinib solution". DailyMed. 2 October 2020. Archived from the original on 30 November 2020. Retrieved 3 November 2020.
    6. 1 2 3 4 5 6 "Xeljanz EPAR". European Medicines Agency (EMA). Archived from the original on 28 October 2020. Retrieved 3 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    7. ↑ "Tofacitinib Use During Pregnancy | Drugs.com". Drugs.com. Archived from the original on 29 November 2020. Retrieved 5 October 2021.
    8. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1168. ISBN 978-0-85711-369-6.
    9. ↑ "Tofacitinib Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 5 October 2021.
    10. 1 2 3 "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. Public Domain This article incorporates text from this source, which is in the public domain.
    11. ↑ "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. Public Domain This article incorporates text from this source, which is in the public domain.
    12. ↑ "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. 27 April 2013. Archived from the original on 17 July 2013. Retrieved 2 August 2013. {{cite news}}: Unknown parameter |vauhthors= ignored (help)
    13. ↑ McKee S (29 June 2018). "EU approves Pfizer's Xeljanz for psoriatic arthritis". PharmaTimes. Archived from the original on 4 December 2020. Retrieved 3 June 2019.
    14. ↑ "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 13-16 May 2019, May 17, 2019". European Medicines Agency. Archived from the original on 17 May 2019. Retrieved 17 May 2019.
    15. ↑ "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. Public Domain This article incorporates text from this source, which is in the public domain.
    16. ↑ 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. Archived from the original on 12 December 2019. Retrieved 15 December 2019.
    17. ↑ "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.
    18. ↑ O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A (April 2013). "Janus kinase inhibitors in autoimmune diseases". Annals of the Rheumatic Diseases. 72 Suppl 2 (suppl 2): ii111-5. doi:10.1136/annrheumdis-2012-202576. PMC 3616338. PMID 23532440.
    19. ↑ FDA Warns of Risk for PE, Death With Higher Dose Tofacitinib (Xeljanz) for RA - Medscape - Feb 25, 2019.
    20. ↑ "Tofacitinib". Drugs in R&D. 10 (4): 271–84. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673.
    21. ↑ Marren AS (2017). "Tofacitinib is not a biologic" (PDF). Annals of Gastroenterology. 30 (1): 134. doi:10.20524/aog.2016.0094. PMC 5198242. PMID 28042254. Archived (PDF) from the original on 8 June 2021. Retrieved 6 August 2021.
    22. ↑ Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, et al. (April 2011). "Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)". Journal of Immunology. 186 (7): 4234–43. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241.
    23. 1 2 3 "Seeking Profit for Taxpayers in Potential of New Drug" Archived 7 May 2021 at the Wayback Machine, Jonathan Weisman, New York Times, 18 March 2013 (subscription firewall)
    24. 1 2 Garber K (January 2013). "Pfizer's first-in-class JAK inhibitor pricey for rheumatoid arthritis market". Nature Biotechnology. 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910. S2CID 33144447. Archived from the original on 29 August 2021. Retrieved 6 August 2021.
    25. ↑ Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. (July 2009). "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo". Arthritis and Rheumatism. 60 (7): 1895–905. doi:10.1002/art.24567. PMID 19565475.
    26. ↑ Herper M (2 March 2011). "Why Pfizer's Biggest Experimental Drug Got A Name Change". Forbes. Archived from the original on 3 March 2011. Retrieved 3 March 2011.
    27. ↑ Moisan A, et al. (2014). "White-to-brown metabolic conversion of human adipocytes by JAK inhibition". Nature Cell Biology. 17 (1): 57–67. doi:10.1038/ncb3075. PMC 4276482. PMID 25487280.
    28. 1 2 Di Lernia V, Bardazzi F (January 2016). "Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis". Drug Design, Development and Therapy. 10: 533–9. doi:10.2147/DDDT.S82599. PMC 4743637. PMID 26889081.
    29. ↑ "Pfizer Provides Update on Global Regulatory Approvals and Launches of Xeljanz (tofacitinib citrate) for the Treatment of Rheumatoid Arthritis". Pfizer. 15 July 2013. Archived from the original on 26 January 2021. Retrieved 3 November 2020.
    30. ↑ Vuitton L, Koch S, Peyrin-Biroulet L (November 2013). "Janus kinase inhibition with tofacitinib: changing the face of inflammatory bowel disease treatment". Current Drug Targets. 14 (12): 1385–91. doi:10.2174/13894501113149990160. PMID 23627915.
    31. ↑ Zand MS (July 2013). "Tofacitinab in renal transplantation". Transplantation Reviews. 27 (3): 85–9. doi:10.1016/j.trre.2013.04.001. PMC 3713609. PMID 23849222.
    32. ↑ Kirk AD, Knechtle SJ, Larsen CP, Madsen JC, Pearson TC, Webber SA (21 July 2014). Textbook of Organ Transplantation Set. John Wiley & Sons. pp. 245–. ISBN 978-1-118-88962-6. Archived from the original on 29 August 2021. Retrieved 6 August 2021.
    33. ↑ Wojciechowski D, Vincenti F (September 2013). "Tofacitinib in kidney transplantation". Expert Opinion on Investigational Drugs. 22 (9): 1193–9. doi:10.1517/13543784.2013.811231. PMID 23841583. S2CID 6768856.
    34. ↑ Myrvang H (June 2012). "Transplantation: Tofacitinib safe and effective in renal transplant recipients". Nature Reviews. Nephrology. 8 (8): 432. doi:10.1038/nrneph.2012.120. PMID 22735765. S2CID 9819931. Archived from the original on 29 August 2021. Retrieved 6 August 2021.
    35. ↑ 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.
    36. ↑ Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, et al. (October 2015). "Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials". The British Journal of Dermatology. 173 (4): 949–61. doi:10.1111/bjd.14018. PMID 26149717.
    37. 1 2 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. S2CID 6087705. Archived from the original on 29 August 2021. Retrieved 6 August 2021.
    38. ↑ "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. Archived from the original on 1 October 2020. Retrieved 6 August 2021.
    39. ↑ 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.
    40. ↑ 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.
    41. ↑ 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.
    42. ↑ Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al. (September 2016). "Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata". JCI Insight. 1 (15): e89776. doi:10.1172/jci.insight.89776. PMC 5033755. PMID 27699252.
    43. ↑ 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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