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
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral, topical
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
Molecular mass 306.37 g/mol
  • C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
  • InChI=1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1 YesY
  • Key:HFNKQEVNSGCOJV-OAHLLOKOSA-N YesY
 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

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

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

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

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

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 HIGHLIGHTS OF PRESCRIBING INFORMATION [1]
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.}
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ ASCO Annual Meeting 2011: JAK Inhibitor Ruxolitinib Demonstrates Significant Clinical Benefit in Myelofibrosis Archived November 21, 2011 at the Wayback Machine
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ FDA approval letter. [2]
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found. 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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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