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Ruxolitinib

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Ruxolitinib
150px
Systematic (IUPAC) name
(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
Clinical data
Trade names Jakafi, Jakavi
AHFS/Drugs.com monograph
MedlinePlus a612006
Licence data EMA:Link, US FDA:link
  • AU: C
  • US: C (Risk not ruled out)
Oral, topical
Pharmacokinetic data
Bioavailability 95%[1]
Protein binding 97%[1]
Metabolism Hepatic (mainly CYP3A4-mediated)[1]
Half-life 2.8-3 hours[1]
Excretion Urine (74%), faeces (22%)[1]
Identifiers
941678-49-5 7pxY
L01XE18
ChemSpider 25027389 7pxY
UNII 82S8X8XX8H 7pxY
ChEMBL CHEMBL1789941 7pxN
Synonyms INCB018424, INC424
Chemical data
Formula C17H18N6
306.37 g/mol
 14pxN (what is this?)  (verify)

Ruxolitinib (INC424, INCB18424, trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow.[2][3] It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer),[4] for polycythemia vera,[4] for plaque psoriasis, and for alopecia areata.[5]

Mechanism of action

Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes JAK1 and JAK2 of this enzyme.[6][7] Ruxolitinib inhibits dysregulated JAK signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.

Side effects

Immunologic side effects have included herpes zoster (shingles; 1.9%) and case reports of opportunistic infections.[8] Metabolic side effects have included weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%).[citation needed] Other common adverse events are anemia (low red blood cell count) and thrombocytopenia (low blood platelet count). Grade 3 to 4 anemia occurs in up to 45% of patients and grade 3 to 4 thrombocytopenia occurs in 10% to 15% of cases, and requires medical intervention to return to near-baseline levels.[9]

Clinical trials and approval

The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.[10][11][12][13]

In November 2011, ruxolitinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.[14]

Economics

Some analysts believe this to be a potential blockbuster drug.[4] As of the end of March 2012, and according to an Incyte spokesman, approximately 1000 physicians had prescribed the drug in the United States, out of a total 6500 hematologists and oncologists nationwide.[4]

References

  1. ^ a b c d e "Jakafi (ruxolitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014. 
  2. ^ Mesa, Ruben A.; Yasothan, Uma; Kirkpatrick, Peter (2012). "Ruxolitinib". Nature Reviews Drug Discovery 11 (2): 103–4. PMID 22293561. doi:10.1038/nrd3652. 
  3. ^ Harrison, C; Mesa, R; Ross, D; Mead, A; Keohane, C; Gotlib, J; Verstovsek, S (2013). "Practical management of patients with myelofibrosis receiving ruxolitinib". Expert Review of Hematology 6 (5): 511–23. PMID 24083419. doi:10.1586/17474086.2013.827413. 
  4. ^ a b c d Natoli, Cori Anne (May 5, 2012), "Incyte looks to ride on drug's success", The News Journal, retrieved May 6, 2012 
  5. ^ Xing, Luzhou et al. (2014). "Letter, Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition". Nature Medicine. doi:10.1038/nm.3645.  Advance online publication retrieved 17 August 2014
  6. ^ Mesa, RA (2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis". IDrugs : the investigational drugs journal 13 (6): 394–403. PMID 20506062.  edit
  7. ^ Pardanani, A.; Tefferi, A. (2011). "Targeting myeloproliferative neoplasms with JAK inhibitors". Current Opinion in Hematology 18 (2): 105–10. PMID 21245760. doi:10.1097/MOH.0b013e3283439964.  edit
  8. ^ Wysham, NG; Allada G; Sullivan DR (2013). "An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor.". Chest 143 (5): 1478–9. PMID 23648912. doi:10.1378/chest.12-1604. 
  9. ^ Hobbs, GS; Rampal RK (2015). "JAK2 Mutations and JAK Inhibitors in the Management of Myeloproliferative Neoplasms [1]". Contemporary Oncology 7 (1): 22–28. 
  10. ^ Harrison, C.; Kiladjian, J. J.; Al-Ali, H. K.; Gisslinger, H.; Waltzman, R.; Stalbovskaya, V.; McQuitty, M.; Hunter, D. S.; Levy, R.; Knoops, L.; Cervantes, F.; Vannucchi, A. M.; Barbui, T.; Barosi, G. (2012). "JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis". New England Journal of Medicine 366 (9): 787–798. PMID 22375970. doi:10.1056/NEJMoa1110556.  edit
  11. ^ Verstovsek, S.; Mesa, R. A.; Gotlib, J.; Levy, R. S.; Gupta, V.; Dipersio, J. F.; Catalano, J. V.; Deininger, M.; Miller, C.; Silver, R. T.; Talpaz, M.; Winton, E. F.; Harvey Jr, J. H.; Arcasoy, M. O.; Hexner, E.; Lyons, R. M.; Paquette, R.; Raza, A.; Vaddi, K.; Erickson-Viitanen, S.; Koumenis, I. L.; Sun, W.; Sandor, V.; Kantarjian, H. M. (2012). "A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis". New England Journal of Medicine 366 (9): 799–807. PMID 22375971. doi:10.1056/NEJMoa1110557.  edit
  12. ^ Tefferi, A. (2012). "Challenges Facing JAK Inhibitor Therapy for Myeloproliferative Neoplasms". New England Journal of Medicine 366 (9): 844–846. PMID 22375977. doi:10.1056/NEJMe1115119.  edit
  13. ^ ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis
  14. ^ "FDA Approves Incyte's Jakafi(TM) (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Retrieved 2012-01-02.