Ruxolitinib

Ruxolitinib
Names
PronunciationJakafi /ˈdʒækəfaɪ/ JAK-ə-fye
Trade namesJakafi, Jakavi
Other namesINCB018424, INC424
IUPAC name
  • (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
Clinical data
Drug classKinase inhibitor[1]
Main usesMyelofibrosis, polycythemia vera (PCV), graft-versus-host disease[1]
Side effectsLow platelets, low red blood cells, low neutrophils, bleeding, liver problems, abnormal lipids[2]
InteractionsCYP3A4 inhibitors, fluconazole[1]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    Typical dose5 to 20 mg BID[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa612006
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability95%[4]
    Protein binding97%[4]
    MetabolismLiver (mainly CYP3A4-mediated)[4]
    Elimination half-life2.8-3 hours[4]
    ExcretionUrine (74%), faeces (22%)[4]
    Chemical and physical data
    FormulaC17H18N6
    Molar mass306.373 g·mol−1
    3D model (JSmol)
    SMILES
    • C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
    InChI
    • 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 checkY
    • Key:HFNKQEVNSGCOJV-OAHLLOKOSA-N checkY

    Ruxolitinib, sold under the brand names Jakafi and Jakavi, is a medication used to treat myelofibrosis, polycythemia vera (PCV), and graft-versus-host disease (GvHD).[1] It is used in PCV when hydroxyurea is not sufficient and in GvHD that is unresponsive to other measures.[1] It is taken by mouth.[1]

    Common side effects include low platelets, low red blood cells, low neutrophils, bleeding, liver problems, and abnormal lipids.[2] Other side effects may include infection, skin cancer, blood clots, and heart disease.[1] Use in pregnancy may harm the baby.[5] It is a kinase inhibitor.[1]

    Ruxolitinib was approved for medical use in the United States in 2011 and Europe in 2012.[1][2] In the United States it costs about 15,800 USD per month as of 2021.[6] In the United Kingdom this amount costs the NHS about £3,000.[5]

    Medical uses

    In the United States and the European Union, ruxolitinib is indicated for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis or post-essential thrombocythaemia myelofibrosis.[3] It is also indicated for the treatment of adults with polycythaemia vera who are resistant to or intolerant of hydroxyurea.[3]

    In the United States, ruxolitinib is also indicated for the treatment of steroid-refractory acute graft-versus-host disease in people who are twelve years of age and older.[1]

    Dosage

    It is used at a dose of 5 mg to 20 mg twice per day.[1]

    Side effects

    In myelofibrosis, the most common side effects include thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), neutropenia (low levels of neutrophils), urinary tract infections (infection of the structures that carry urine), bleeding, bruising, weight gain, hypercholesterolaemia (high blood cholesterol levels), dizziness, headache and raised liver enzyme levels.[3]

    In polycythaemia vera, the most common side effects include thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), bleeding, bruising, hypercholesterolaemia (high blood cholesterol levels), hypertriglyceridemia (high blood fat levels), dizziness, raised liver enzyme levels and high blood pressure.[3]

    In acute graft-versus-host disease, the most common hematologic adverse reactions include anemia, thrombocytopenia, and neutropenia.[1] The most common nonhematologic adverse reactions include infections and edema.[1]

    Immunologic side effects have included herpes zoster (shingles) and case reports of opportunistic infections.[7] Metabolic side effects have included weight gain. Laboratory abnormalities have included alanine transaminase (ALT) abnormalities, aspartate transaminase (AST) abnormalities, and mildly elevated cholesterol levels.[1]

    Mechanism of action

    Ruxolitinib is a janus kinase inhibitor (JAK inhibitor) with selectivity for subtypes JAK1 and JAK2.[8][9] 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.

    History

    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]

    Society and culture

    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][16]

    Names

    It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

    Research

    It is also being investigated for plaque psoriasis,[8] alopecia areata,[17] relapsed diffuse large B-cell lymphoma, and peripheral T-cell lymphoma.[18]

    In February 2016, a phase III trial for pancreatic cancer was terminated due to insufficient efficacy.[19]

    Eight weeks-treatment with ruxolitinib blunted senescent cell-mediated inhibition of adipogenesis and increased insulin sensitivity in 22-month-old mice.[20]

    As of September 2019, a clinical trial was in progress to evaluate "Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors".[21]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Jakafi- ruxolitinib tablet". DailyMed. 26 February 2020. Archived from the original on 3 November 2020. Retrieved 16 November 2020.
    2. 1 2 3 "Jakavi". Archived from the original on 12 November 2020. Retrieved 19 October 2021.
    3. 1 2 3 4 5 "Jakavi EPAR". European Medicines Agency (EMA). Archived from the original on 12 November 2020. Retrieved 16 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    4. 1 2 3 4 5 "Jakafi (ruxolitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 12 December 2018. Retrieved 16 February 2014.
    5. 1 2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1056. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    6. ↑ "Jakafi Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 October 2021. Retrieved 19 October 2021.
    7. ↑ Wysham NG, Sullivan DR, Allada G (May 2013). "An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor". Chest. 143 (5): 1478–1479. doi:10.1378/chest.12-1604. PMC 5991580. PMID 23648912.
    8. 1 2 Mesa RA (June 2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis". IDrugs. 13 (6): 394–403. PMID 20506062.
    9. ↑ Pardanani A, Tefferi A (March 2011). "Targeting myeloproliferative neoplasms with JAK inhibitors". Current Opinion in Hematology. 18 (2): 105–10. doi:10.1097/MOH.0b013e3283439964. PMID 21245760. S2CID 2059415.
    10. ↑ Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. (March 2012). "JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis". The New England Journal of Medicine. 366 (9): 787–98. doi:10.1056/NEJMoa1110556. hdl:2158/605459. PMID 22375970.
    11. ↑ Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. (March 2012). "A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis". The New England Journal of Medicine. 366 (9): 799–807. doi:10.1056/NEJMoa1110557. PMC 4822164. PMID 22375971.
    12. ↑ Tefferi A (March 2012). "Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms". The New England Journal of Medicine. 366 (9): 844–6. 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. Archived from the original on 2017-06-24. Retrieved 2012-01-02.
    15. ↑ Kaminskas E (4 December 2014). "Supplemental FDA approval letter for Jakafi (ruxolitinib) tablets" (PDF). U.S. Food and Drug Administration. Archived (PDF) from the original on 11 April 2021. Retrieved 21 June 2021.
    16. ↑ Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. (January 2015). "Ruxolitinib versus standard therapy for the treatment of polycythemia vera". The New England Journal of Medicine. 372 (5): 426–35. doi:10.1056/NEJMoa1409002. PMC 4358820. PMID 25629741.
    17. ↑ Falto-Aizpurua L, Choudhary S, Tosti A (December 2014). "Emerging treatments in alopecia". Expert Opinion on Emerging Drugs. 19 (4): 545–56. doi:10.1517/14728214.2014.974550. PMID 25330928. S2CID 21604470.
    18. ↑ Clinical trial number NCT01431209 for "Ruxolitinib Phosphate (Oral JAK Inhibitor INCB18424) in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell or Peripheral T-Cell Non-Hodgkin Lymphoma" at ClinicalTrials.gov
    19. ↑ House DW (February 2016). "Incyte bags late-stage development of Jakafi for solid tumors; shares down 10% premarket". Seeking Alpha. Archived from the original on 2016-10-10. Retrieved 2021-06-21.
    20. ↑ Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. (December 2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007.
    21. ↑ Clinical trial number NCT03610971 for "Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors" at ClinicalTrials.gov
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