Chemistry:Tofacitinib

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Short description: Medication
Tofacitinib
Tofacitinib.svg
Clinical data
Trade namesXeljanz, Jaquinus, Tofacinix, Others
Other namesCP-690550
AHFS/Drugs.comMonograph
MedlinePlusa613025
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classJanus kinase (JAK) inhibitor
ATC code
Legal status
Legal status
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
Chemical and physical data
FormulaC16H20N6O
Molar mass312.377 g·mol−1
3D model (JSmol)

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.[6][7][8] It is a janus kinase (JAK) inhibitor,[6][7] discovered and developed by the National Institutes of Health and Pfizer.

Common side effects include diarrhea, headache, and high blood pressure.[8] Serious side effects may include infections, cancer, and pulmonary embolism.[8][9] 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.[10] The U.S. Food and Drug Administration (FDA) also released warnings about the risk of blood clots.[11][12][13] 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.[14]

It was approved for medical use in the United States in November 2012.[15] The extended release version was approved in February 2016.[16] It is available as a generic medication.[17]

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."[18][6]

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.[7] It can be given as monotherapy in case of intolerance to methotrexate or when treatment with MTX is inappropriate.[7]

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."[19] 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,[20] although by 2018, the European Commission had approved it.[21] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[6]

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").[6]

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.[18] 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.[6]

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.[22]

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.[23]

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.[24]

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).[25] 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.[25] 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."[25] 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.[26]

The drug was coded as CP-690,550[27] during development. Its original recommended International nonproprietary name (rINN) was tasocitinib,[28] 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.[6][15]

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.[29]

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.[18] 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.[30]

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.[31]

In December 2021, the FDA approved tofacitinib for the treatment of adults with active ankylosing spondylitis.[32]

As of June 2021, tofacitinib is available as a generic medicine in the US.[33][34]

Society and culture

Names

Tofacitinib is marketed as Xeljanz except for Russia, where it is marketed as Jaquinus.[35]

Research

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.[36][37][38][39]

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.[30][40][41] [42] In particular, a ten-mg, twice-daily dose of tofacitinib was shown to be not inferior to etanercept 50 mg, subcutaneously, twice weekly.[41] In October 2015, the FDA rejected approval of tofacitinib for the treatment of psoriasis due to safety concerns.[43]

Alopecia areata

Based on preclinical studies in a mouse model of the disease,[44] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports[45][46] suggested potential efficacy, as did a phase II open-label clinical trial,[47] published in tandem with a phase II clinical trial showing the same for ruxolitinib.[48]

Vitiligo

In a June 2015 case report, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[49]

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.[50]

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.[51][52]

Ulcerative colitis

As of November 2013 it was studied for treatment of inflammatory bowel disease.[53][42]The FDA approved tofacitinib in May 2018 for treatment of ulcerative colitis.[19]

References

  1. ↑ "Tofacitinib Use During Pregnancy". 15 April 2020. https://www.drugs.com/pregnancy/tofacitinib.html. 
  2. ↑ "Xeljanz/Xeljanz XR (Pfizer Australia Pty Ltd)". 16 February 2023. https://www.tga.gov.au/resources/prescription-medicines-registrations/xeljanzxeljanz-xr-pfizer-australia-pty-ltd. 
  3. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015. 
  4. ↑ "10 mg film-coated tablets - Summary of Product Characteristics (SmPC)". 13 October 2020. https://www.medicines.org.uk/emc/product/9410/smpc. 
  5. ↑ "Xeljanz 11 mg prolonged release tablets - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/11086/smpc. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Xeljanz- tofacitinib tablet, film coated Xeljanz XR- tofacitinib tablet, film coated, extended release Xeljanz- tofacitinib solution". 2 October 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Xeljanz EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/xeljanz.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ 8.0 8.1 8.2 "Tofacitinib Citrate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/tofacitinib-citrate.html. 
  9. ↑ "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". https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM632016.  This article incorporates text from this source, which is in the public domain.
  10. ↑ "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 13-16 May 2019, May 17, 2019". European Medicines Agency. 17 May 2019. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-13-16-may-2019. 
  11. ↑ "Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose". 26 July 2019. https://www.fda.gov/about-fda/medical-product-safety-information/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-due-increased-risk-blood-clots-and-death.  This article incorporates text from this source, which is in the public domain.
  12. ↑ 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.
  13. ↑ "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)". 15 December 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. 
  14. ↑ "Janus kinase inhibitors in autoimmune diseases". Annals of the Rheumatic Diseases 72 (Suppl 2): ii111–ii115. April 2013. doi:10.1136/annrheumdis-2012-202576. PMID 23532440. 
  15. ↑ 15.0 15.1 "Drug Approval Package: Xeljanz (tofacitinib) Tablets NDA #203214". 28 December 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000TOC.cfm. 
  16. ↑ "Drug Approval Package: Xeljanz (tofacitinib) Extended Release (XR) Tablets NDA #208246". 26 June 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208246Orig1s000TOC.cfm. 
  17. ↑ "First Generic Drug Approvals 2023". 30 May 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals. 
  18. ↑ 18.0 18.1 18.2 "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. This article incorporates text from this source, which is in the public domain.
  19. ↑ 19.0 19.1 "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.
  20. ↑ "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. 27 April 2013. https://www.medicalnewstoday.com/articles/259752. 
  21. ↑ "EU approves Pfizer's Xeljanz for psoriatic arthritis" (in en). 29 June 2018. https://www.pharmatimes.com/news/eu_approves_pfizers_xeljanz_for_psoriatic_arthritis_1242439. 
  22. ↑ FDA Warns of Risk for PE, Death With Higher Dose Tofacitinib (Xeljanz) for RA - Medscape - 25 February 2019.
  23. ↑ Adis Editorial (2010). "Tofacitinib". Drugs in R&D 10 (4): 271–284. doi:10.2165/11588080-000000000-00000. PMID 21171673. 
  24. ↑ "Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)". Journal of Immunology 186 (7): 4234–4243. April 2011. doi:10.4049/jimmunol.1003668. PMID 21383241. 
  25. ↑ 25.0 25.1 25.2 "Seeking Profit for Taxpayers in Potential of New Drug". New York Times. 18 March 2013. https://www.nytimes.com/2013/03/19/business/questions-for-public-private-pact-that-led-to-xeljanz.html. 
  26. ↑ "Pfizer's first-in-class JAK inhibitor pricey for rheumatoid arthritis market". Nature Biotechnology 31 (1): 3–4. January 2013. doi:10.1038/nbt0113-3. PMID 23302910. 
  27. ↑ "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): 1895–1905. July 2009. doi:10.1002/art.24567. PMID 19565475. 
  28. ↑ "Why Pfizer's Biggest Experimental Drug Got A Name Change". Forbes. 2 March 2011. https://blogs.forbes.com/matthewherper/2011/03/02/why-pfizers-biggest-experimental-drug-got-a-name-change/. 
  29. ↑ "White-to-brown metabolic conversion of human adipocytes by JAK inhibition". Nature Cell Biology 17 (1): 57–67. January 2015. doi:10.1038/ncb3075. PMID 25487280. 
  30. ↑ 30.0 30.1 "Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis". Drug Design, Development and Therapy 10: 533–539. January 2016. doi:10.2147/DDDT.S82599. PMID 26889081. 
  31. ↑ "U.S. FDA Approves Pfizer's Xeljanz (tofacitinib) for the Treatment of Active Polyarticular Course Juvenile Idiopathic Arthritis". Pfizer (Press release). Retrieved 2023-08-21.
  32. ↑ "U.S. FDA Approves Pfizer's Xeljanz (tofacitinib) for the Treatment of Active Ankylosing Spondylitis". Pfizer (Press release). Retrieved 2023-08-21.
  33. ↑ "Tofacitinib citrate: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212943. 
  34. ↑ "Tofacitinib: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=214264. 
  35. ↑ "Pfizer Provides Update on Global Regulatory Approvals and Launches of Xeljanz (tofacitinib citrate) for the Treatment of Rheumatoid Arthritis". Pfizer (Press release). 15 July 2013. Retrieved 3 November 2020.
  36. ↑ Textbook of Organ Transplantation Set. John Wiley & Sons. 21 July 2014. pp. 245–. ISBN 978-1-118-88962-6. https://books.google.com/books?id=GzMWBAAAQBAJ&pg=PA245. 
  37. ↑ "Tofacitinib in kidney transplantation". Expert Opinion on Investigational Drugs 22 (9): 1193–1199. September 2013. doi:10.1517/13543784.2013.811231. PMID 23841583. 
  38. ↑ "Transplantation: Tofacitinib safe and effective in renal transplant recipients". Nature Reviews. Nephrology 8 (8): 432. June 2012. doi:10.1038/nrneph.2012.120. PMID 22735765. 
  39. ↑ "Current state of renal transplant immunosuppression: Present and future". World Journal of Transplantation 2 (4): 51–68. August 2012. doi:10.5500/WJT.v2.i4.51. PMID 24175197. 
  40. ↑ "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): 949–961. October 2015. doi:10.1111/bjd.14018. PMID 26149717. 
  41. ↑ 41.0 41.1 "Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial". Lancet 386 (9993): 552–561. August 2015. doi:10.1016/S0140-6736(14)62113-9. PMID 26051365. 
  42. ↑ 42.0 42.1 "Tofacitinab in renal transplantation". Transplantation Reviews 27 (3): 85–89. July 2013. doi:10.1016/j.trre.2013.04.001. PMID 23849222. 
  43. ↑ "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.
  44. ↑ "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition". Nature Medicine 20 (9): 1043–1049. September 2014. doi:10.1038/nm.3645. PMID 25129481. 
  45. ↑ "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. December 2014. doi:10.1038/jid.2014.260. PMID 24940651. 
  46. ↑ "Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers". Experimental Dermatology 25 (8): 642–643. August 2016. doi:10.1111/exd.13060. PMID 27119625. 
  47. ↑ "Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata". JCI Insight 1 (15): e89776. September 2016. doi:10.1172/jci.insight.89776. PMID 27699252. 
  48. ↑ "Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata". JCI Insight 1 (15): e89790. September 2016. doi:10.1172/jci.insight.89790. PMID 27699253. 
  49. ↑ "Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy". JAMA Dermatology 151 (10): 1110–1112. October 2015. doi:10.1001/jamadermatol.2015.1520. PMID 26107994. 
  50. ↑ "Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate". Journal of the American Academy of Dermatology 73 (3): 395–399. September 2015. doi:10.1016/j.jaad.2015.06.045. PMID 26194706. 
  51. ↑ "Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study". Annals of the Rheumatic Diseases 80 (8): 1004–1013. August 2021. doi:10.1136/annrheumdis-2020-219601. PMID 33906853. 
  52. ↑ "Effect of tofacitinib on pain, fatigue, health-related quality of life and work productivity in patients with active ankylosing spondylitis: results from a phase III, randomised, double-blind, placebo-controlled trial". RMD Open 8 (2): e002253. June 2022. doi:10.1136/rmdopen-2022-002253. PMID 35654457. 
  53. ↑ "Janus kinase inhibition with tofacitinib: changing the face of inflammatory bowel disease treatment". Current Drug Targets 14 (12): 1385–1391. November 2013. doi:10.2174/13894501113149990160. PMID 23627915. 

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