Ruxolitinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

• Sicherheit

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Ruxolitinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  In November 2011, the U.S. FDA approved ruxolitinib (INCB018424) for the treatment of patients with intermediate or high-risk myelofibrosis. Ruxolitinib is an ATP-competitive inhibitor of JAK1 and JAK2 (IC_50's of 3.3±1.2 nM and 2.8±1.2 nM, respectively) and inhibition occurs regardless of the JAK2V617F mutational status. Ruxolitinib is a moderately potent inhibitor of the related JAK, TYK2 (IC₅₀=19±3.2 nM) but is selective versus JAK3 (IC₅₀=428±243 nM). It was also selective versus a panel of 26 other kinases at concentrations approximately 100-fold the IC₅₀ of JAK1 and JAK2. Inhibition of JAK1 and JAK2 downregulates the JAK-signal transducer and activator of transcription (STAT) pathway, inhibiting myeloproliferation, inducing apoptosis, and reducing numerous cytokine plasma levels.

• Originator

  Incyte Corporation (United States)

• Charakteristisch

  Class: non-receptor tyrosine kinase
  Treatment: MF, PV, cGVHD
  Oral bioavailability >95%
  Elimination half-life = 3 h
  Protein binding = 97%

• Verwenden

  Ruxolitinib is a selective Janus tyrosine kinase (JAK1 and JAK2) inhibitor used in the treatment of myeloproliferative neoplasms and psoriasis.

• Verwenden

  INCB018424 is the first potent, selective, JAK1/2 inhibitor to enter the clinic with IC50 of 3.3 nM/2.8 nM, >130-fold selectivity for JAK1/2 versus JAK3. Phase 3

• Verwenden

  A JAK family kinase inhibitor of JAK1, JAK2 and JAK3 with IC50s of 2.7 nM, 4.5 nM and 322 nM, respectively

• Verwenden

  Janus-associated kinases (JAKs) are cytoplasmic tyrosine kinases that are required for activating the signaling of certain cytokines and growth factor receptors. A JAK2 gene fusion mutation, JAK2V617F, that causes unchecked activation of various growth factors and cytokines, has been linked to myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Ruxolitinib is a potent ATP mimetic that inhibits both JAK1 and JAK2 with IC50 values of 2.7 and 4.5 nM, respectively and is relatively less selective for JAK3 (IC50 = 322 nM). It can block interleukin-6 (IL-6) signaling (IC50 = 281 nM) and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127 nM). In primary cultures, ruxolitinib preferentially suppresses erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67 nM) versus healthy donors (IC50 > 400 nM). In a mouse model of JAK2V617F+ MPN, 90 mg/kg ruxolitinib reduced splenomegaly, decreased circulating levels of IL-6 and TNF-α, eliminated neoplastic cells, and prolonged survival of the treated animals.[Cayman Chemical]

• Indications

  The JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications.

• Definition

  ChEBI: A pyrazole substituted at position 1 by a 2-cyano-1-cyclopentylethyl group and at position 3 by a pyrrolo[2,3-d]pyrimidin-4-yl group. Used as the phosphate salt for the treatment of patients with intermediate or high-risk myelofibrosis, includ ng primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

• Trademarks

  Jakafi

• Clinical Use

  Tyrosine kinase inhibitor:
  Treatment of disease related splenomegaly or symptoms in patients with primary myelofibrosis (MF), post polycythaemia vera (PV) myelofibrosis or post-essential thrombocythemia myelofibrosis

• target

  JAK1

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: concentration increased by clarithromycin and telithromycin, reduced dose of ruxolitinib; concentration reduced by rifampicin.
  Antifungals: reduce dose of ruxolitinib with fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole.
  Antipsychotics: avoid with clozapine, risk of agranulocytosis.
  Antivirals: reduce dose of ruxolitinib with boceprevir, indinavir, lopinavir, ritonavir, saquinavir and telaprevir.

• Stoffwechsel

  Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9 to produce 2 major and active metabolites. About 74% of a dose is excreted in the urine and about 22% via the faeces.

• Lager

  Store at -20°C

• Einzelnachweise

  [1] VERSTOVSEK S. Therapeutic potential of JAK2 inhibitors.[J]. Hematology. American Society of Hematology. Education Program, 2009: 636-642. DOI:10.1182/asheducation-2009.1.636
  [2] ALFONSO QUINTÁS-CARDAMA. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.[J]. Blood, 2010, 115 15: 3109-3117. DOI:10.1182/blood-2009-04-214957
  [3] JOSHUA N FARR. Targeting cellular senescence prevents age-related bone loss in mice[J]. Nature Medicine, 2017, 23 9: 1072-1079. DOI:10.1038/nm.4385
  [4] QIAN LI. Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.[J]. Oncotarget, 2017: 34687-34697. DOI:10.18632/oncotarget.16670

Ruxolitinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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