Ruxolitinib

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Ruxolitinib
Ruxolitinib2DACS.svg
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
Pregnancy cat.
Legal status
Routes 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
CAS number 941678-49-5 YesY
ATC code L01XE18
ChemSpider 25027389 YesY
UNII 82S8X8XX8H YesY
ChEMBL CHEMBL1789941 N
Synonyms INCB018424, INC424
Chemical data
Formula C17H18N6 
Mol. mass 306.37 g/mol
 N (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 bone marrow cancer.[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[edit]

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[edit]

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]

Clinical trials and approval[edit]

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.[9][10][11][12]

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.[13]

Economics[edit]

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[edit]

  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. doi:10.1038/nrd3652. PMID 22293561. 
  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. doi:10.1586/17474086.2013.827413. PMID 24083419. 
  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): 1. doi:10.1097/MOH.0b013e3283439964. PMID 21245760.  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. doi:10.1378/chest.12-1604. PMID 23648912. 
  9. ^ 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. doi:10.1056/NEJMoa1110556. PMID 22375970.  edit
  10. ^ 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. doi:10.1056/NEJMoa1110557. PMID 22375971.  edit
  11. ^ Tefferi, A. (2012). "Challenges Facing JAK Inhibitor Therapy for Myeloproliferative Neoplasms". New England Journal of Medicine 366 (9): 844–846. doi:10.1056/NEJMe1115119. PMID 22375977.  edit
  12. ^ ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis
  13. ^ "FDA Approves Incyte's Jakafi(TM) (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Retrieved 2012-01-02.