Tofacitinib

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Tofacitinib
Tofacitinib2DACS.svg
Systematic (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
Trade names Xeljanz, Jakvinus
AHFS/Drugs.com entry
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Hepatic (via CYP3A4 and CYP2C19)
Half-life 3 hours
Excretion Urine
Identifiers
CAS number 477600-75-2
ATC code L04AA29
PubChem CID 9926791
DrugBank DB08183
ChemSpider 8102425
UNII 87LA6FU830
ChEBI CHEBI:71200 YesY
ChEMBL CHEMBL221959
Synonyms CP-690550
Chemical data
Formula C16H20N6O 
Mol. mass 312.369 g/mol

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,[1] CP-690550[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and Russia, and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

Mechanism[edit]

It is an inhibitor of the enzyme janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.[3]

Recently it has been shown in a murine model of established arthritis that 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.[4]

Research history[edit]

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).[5] 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.[5] 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."[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.[6]

In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.[6]

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.[7]

Clinical trials[edit]

Rheumatoid arthritis[edit]

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.[8]

The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) and neutropenia.[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[9]

In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.[10]

By April 2011, three phase III trials for RA had reported positive results.[11]

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."[12]

Psoriasis[edit]

As of April 2011 a phase III trial for psoriasis is under way.[11]

Combination with methotrexate[edit]

Tofacitinib can be taken with or without methotrexate.[13]

Alopecia[edit]

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.[14]

Safety and side effects[edit]

Tofacitinib was not approved by European regulatory agencies because of concerns over efficacy and safety.[15] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[16]

Warnings and precautions[edit]

Xeljanz is required 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.[12] 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.[16]

Adverse reactions[edit]

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").[16]

References[edit]

  1. ^ Herper, Matthew (2 March 2011). "Why Pfizer’s Biggest Experimental Drug Got A Name Change". Forbes. Retrieved 3 March 2011. 
  2. ^ Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (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 & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475.  edit
  3. ^ "Tasocitinib". Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673.  edit
  4. ^ Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O'Shea, J. J. (2011). "Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)". J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241.  edit
  5. ^ a b c "Seeking Profit for Taxpayers in Potential of New Drug", Jonathan Weisman, New York Times, March 18, 2013
  6. ^ a b Ken Garber (9 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. 
  7. ^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
  8. ^ a b "EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain". MedPage Today. June 2009. Retrieved 9 February 2011. 
  9. ^ ClinicalTrials.gov NCT00413699 Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis
  10. ^ Matthew Herper. "Pfizer’s Key Drug Walks A Tightrope". Forbes. 
  11. ^ a b "Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA". 28 Apr 2011. 
  12. ^ a b "FDA approves Xeljanz for rheumatoid arthritis". 6 Nov 2012. 
  13. ^ Drugs.com: entry
  14. ^ "Hairless man grows full head of hair in yale arthritis drug trial". 19 Jun 2014. 
  15. ^ Nordqvist, Christian (27 April 2013). "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. Retrieved 2 August 2013. 
  16. ^ a b c ""XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com"".