Ruxolitinib

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Ruxolitinib
Ruxolitinib skeletal.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
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
Oral, topical
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%[1]
Protein binding 97%[1]
Metabolism Hepatic (mainly CYP3A4-mediated)[1]
Biological half-life 2.8-3 hours[1]
Excretion Urine (74%), faeces (22%)[1]
Identifiers
CAS Number 941678-49-5 YesY
ATC code L01XE18 (WHO)
IUPHAR/BPS 5688
ChemSpider 25027389 YesY
UNII 82S8X8XX8H YesY
ChEMBL CHEMBL1789941 N
Synonyms INCB018424, INC424
PDB ligand ID RXT (PDBe, RCSB PDB)
Chemical data
Formula C17H18N6
Molar mass 306.37 g/mol
 NYesY (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] and for polycythemia vera (PCV) when there has been an inadequate response to or intolerance of hydroxyurea.[4][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]

Side effects include thrombocytopenia (low blood platelet count), anemia (low red blood cell count) and neutropenia; risk of infection; symptom exacerbation if the medication is interrupted or discontinued; and non-melanoma skin cancer.[4][8]

Immunologic side effects have included herpes zoster (shingles) and case reports of opportunistic infections.[9] Metabolic side effects have included weight gain. Laboratory abnormalities have included alanine transaminase (ALT) abnormalities, aspartate transaminase (AST) abnormalities, and mildly elevated cholesterol levels.[4]

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 and relieving debilitating symptoms.[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]

In 2014, it was approved in polycythemia vera (PCV) when there has been an inadequate response to or intolerance of hydroxyurea, based on the RESPONSE trial.[15][5]

Research[edit]

It is also being investigated for plaque psoriasis,[6] and for alopecia areata.[16]

In Feb 2016, a phase III trial for pancreatic cancer was terminated due to insufficient efficacy.[17]

Eight weeks-treatment with ruxolitinib blunted senescent cell-mediated inhibition of adipogenesis and increased insulin sensitivity in 22-month-old mice.[18]

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 HIGHLIGHTS OF PRESCRIBING INFORMATION [1]
  5. ^ a b Vannucchi AM, Kiladjian JJ, Griesshammer M et al. (2015). "Ruxolitinib versus standard therapy for the treatment of polycythemia vera". N. Engl. J. Med. 372 (5): 426–35. doi:10.1056/NEJMoa1409002. PMC 4358820. PMID 25629741. 
  6. ^ a b Mesa RA (2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis". IDrugs 13 (6): 394–403. PMID 20506062. }
  7. ^ Pardanani, A.; Tefferi, A. (2011). "Targeting myeloproliferative neoplasms with JAK inhibitors". Current Opinion in Hematology 18 (2): 105–10. doi:10.1097/MOH.0b013e3283439964. PMID 21245760. 
  8. ^ Hobbs, GS; Rampal RK (2015). "JAK2 Mutations and JAK Inhibitors in the Management of Myeloproliferative Neoplasms". Contemporary Oncology 7 (1): 22–28. 
  9. ^ 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. 
  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. doi:10.1056/NEJMoa1110556. PMID 22375970. 
  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. doi:10.1056/NEJMoa1110557. PMID 22375971. 
  12. ^ 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. 
  13. ^ ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis Archived November 21, 2011, at the Wayback Machine.
  14. ^ "FDA Approves Incyte's Jakafi (ruxolitinib) for Patients with Myelofibrosis" (Press release). Incyte. Retrieved 2012-01-02. 
  15. ^ FDA approval letter. [2]
  16. ^ Xing, Luzhou; et al. (2014). "Letter, 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.  Advance online publication retrieved 17 August 2014
  17. ^ Incyte bags late-stage development of Jakafi for solid tumors; shares down 10% premarket. Feb 2016
  18. ^ Xu, Ming; Palmer, Allyson K; Ding, Husheng; Weivoda, Megan M; Pirtskhalava, Tamar; White, Thomas A; Sepe, Anna; Johnson, Kurt O; Stout, Michael B; Giorgadze, Nino; Jensen, Michael D; Lebrasseur, Nathan K; Tchkonia, Tamar; Kirkland, James L (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". ELife 4. doi:10.7554/eLife.12997.