Ruxolitinib
Identification
- Name
- Ruxolitinib
- Accession Number
- DB08877 (DB06164)
- Type
- Small Molecule
- Groups
- Approved
- Description
Ruxolitinib is a janus-associated kinase inhibitor indicated to treat bone marrow cancer, specifically intermediate or high-risk myelofibrosis. FDA approved on November 16, 2011.
- Structure
Structure for Ruxolitinib (DB08877)
- Synonyms
- Ruxolitinib
- External IDs
- INC-424 / INC424 / INCB 18424 / INCB-018424 / INCB-18424 / INCB018424 / INCB18424 / INCB424
- Product Ingredients
Ingredient UNII CAS InChI Key Ruxolitinib phosphate 436LRU32H5 1092939-17-7 JFMWPOCYMYGEDM-XFULWGLBSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataJakafi Tablet 15.0 mg/1 Oral Incyte Corporation 2011-11-16 Not applicable US 
Jakafi Tablet 10.0 mg/1 Oral Incyte Corporation 2011-11-16 Not applicable US Jakafi Tablet 5.0 mg/1 Oral Incyte Corporation 2011-11-16 Not applicable US Jakafi Tablet 25.0 mg/1 Oral Incyte Corporation 2011-11-16 Not applicable US Jakafi Tablet 20.0 mg/1 Oral Incyte Corporation 2011-11-16 Not applicable US Jakavi Tablet 20 mg Oral Novartis 2012-07-19 Not applicable Canada 
Jakavi Tablet 20 mg Oral Novartis Europharm Limited 2012-08-23 Not applicable EU 
Jakavi Tablet 5 mg Oral Novartis Europharm Limited 2012-08-23 Not applicable EU Jakavi Tablet 10 mg Oral Novartis Europharm Limited 2012-08-23 Not applicable EU Jakavi Tablet 5 mg Oral Novartis Europharm Limited 2012-08-23 Not applicable EU Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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- Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Drugs that are Mainly Renally Excreted
- Immunosuppressive Agents
- Janus Kinases, antagonists & inhibitors
- Kinase Inhibitor
- Myelosuppressive Agents
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- UNII
- 82S8X8XX8H
- CAS number
- 941678-49-5
- Weight
- Average: 306.365
Monoisotopic: 306.159294606 - Chemical Formula
- C17H18N6
- InChI Key
- HFNKQEVNSGCOJV-OAHLLOKOSA-N
- 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
- IUPAC Name
- (3R)-3-cyclopentyl-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)propanenitrile
- SMILES
- N#CC[C@H](C1CCCC1)N1C=C(C=N1)C1=C2C=CNC2=NC=N1
Pharmacology
- Indication
Treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis. [Lexicomp] Myeolofibrosis is the proliferation of abnormal bone marrow stem cells which cause fibrosis (the excessive formation of connective tissue).
- Associated Conditions
- Pharmacodynamics
The mean half-maximal inhibitory concentration (IC50) for JAK 1 and JAK 2 are 2.8 nmol/L and 3.3 nmol/L respectively. After administration of ruxolitinib, a decrease in levels of phosphorylated STAT (marker for JAK activity) in a dose-dependent manner can be observed. Pharmacodynamic resistance has not been observed.
- Mechanism of action
Ruxolitinib is a kinase inhibitor that is selective for the Janus Associated Kinases (JAK) 1 and 2. These kinases are responsible for the mediation of cytokine and growth factor signalling which in turn effect immune function and hematopoiesis. The signalling process involves signal transducers and transcription activators (STAT) which modulate gene expression. Patients with myelofibrosis have abnormal JAK1 and JAK2 activity thus ruxolitinib works to regulate this.
Target Actions Organism ATyrosine-protein kinase JAK1 inhibitorHumans ATyrosine-protein kinase JAK2 inhibitorHumans - Absorption
Absorption is rapid and is not affected by food. Cmax, 15 mg, healthy subject = 649 nmol/L; Tmax, 15 mg, healthy subject = 1.5 hours; Ruxolitinib does not accumulate significantly.
- Volume of distribution
Terminal phase volume of distribution, 15 mg, healthy subject = 76.6 L.
- Protein binding
97% protein bound, primarily to albumin.
- Metabolism
Ruxolitinib is metabolized by CYP3A4. Less potent active metabolites forms as a result.
- Route of elimination
Eliminated via urine (74%, <1% as unchanged drug) and feces (22%, <1% as unchanged drug).
- Half life
Mean elimination half-life, 15 mg, healthy subject = 2.8 hours.
- Clearance
15 mg, healthy subject = 18.7 L/h.
- Toxicity
Thrombocytopenia was the dose-limiting toxicity.
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Learn moreStructured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Learn moreStructured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Learn moreInteractions
- Drug Interactions
Drug Interaction Unlock Additional Data(R)-warfarin The metabolism of Ruxolitinib can be decreased when combined with (R)-warfarin. (S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Ruxolitinib. 3,5-diiodothyropropionic acid The therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Ruxolitinib. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Ruxolitinib. 5-androstenedione The metabolism of Ruxolitinib can be decreased when combined with 5-androstenedione. 6-Deoxyerythronolide B The metabolism of Ruxolitinib can be decreased when combined with 6-Deoxyerythronolide B. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be decreased when combined with Ruxolitinib. 7-ethyl-10-hydroxycamptothecin The metabolism of Ruxolitinib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be decreased when combined with Ruxolitinib. Abacavir Abacavir may decrease the excretion rate of Ruxolitinib which could result in a higher serum level. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionEvidence Level
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Take without regards to meals
References
- General References
- Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013]
- Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804]
- External Links
- KEGG Drug
- D09959
- PubChem Compound
- 25126798
- PubChem Substance
- 175427129
- ChemSpider
- 25027389
- BindingDB
- 50355501
- ChEBI
- 66919
- ChEMBL
- CHEMBL1789941
- PharmGKB
- PA166123386
- HET
- RXT
- Wikipedia
- Ruxolitinib
- ATC Codes
- L01XE18 — Ruxolitinib
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- PDB Entries
- 4u5j
- FDA label
- Download (399 KB)
- MSDS
- Download (210 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Tablet Oral 10.0 mg/1 Tablet Oral 15.0 mg/1 Tablet Oral 20.0 mg/1 Tablet Oral 25.0 mg/1 Tablet Oral 5.0 mg/1 Tablet Oral 10 mg Tablet Oral 15 mg Tablet Oral 20 mg Tablet Oral 5 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Unlock Additional DataUS7598257 No 2009-10-06 2027-12-24 US US8822481 No 2014-09-02 2028-06-12 US US8829013 No 2014-09-09 2028-06-12 US US9079912 No 2015-07-14 2026-12-12 US US8415362 No 2013-04-09 2027-12-24 US US8722693 No 2014-05-13 2028-06-12 US US9662335 No 2017-05-30 2026-12-12 US Additional Data Available- Filed On
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Soluble in aqueous buffers across a pH of 1-8 FDA label. - Predicted Properties
Property Value Source Water Solubility 0.116 mg/mL ALOGPS logP 2.94 ALOGPS logP 2.48 ChemAxon logS -3.4 ALOGPS pKa (Strongest Acidic) 13.89 ChemAxon pKa (Strongest Basic) 5.51 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 83.18 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 98.01 m3·mol-1 ChemAxon Polarizability 33.04 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9673 Caco-2 permeable - 0.5198 P-glycoprotein substrate Non-substrate 0.7838 P-glycoprotein inhibitor I Non-inhibitor 0.8228 P-glycoprotein inhibitor II Inhibitor 0.7092 Renal organic cation transporter Non-inhibitor 0.5098 CYP450 2C9 substrate Non-substrate 0.8394 CYP450 2D6 substrate Non-substrate 0.8075 CYP450 3A4 substrate Non-substrate 0.6535 CYP450 1A2 substrate Inhibitor 0.6426 CYP450 2C9 inhibitor Non-inhibitor 0.7731 CYP450 2D6 inhibitor Non-inhibitor 0.9208 CYP450 2C19 inhibitor Non-inhibitor 0.6689 CYP450 3A4 inhibitor Non-inhibitor 0.6655 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5753 Ames test AMES toxic 0.5681 Carcinogenicity Non-carcinogens 0.9308 Biodegradation Not ready biodegradable 0.9917 Rat acute toxicity 2.5724 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.633 hERG inhibition (predictor II) Non-inhibitor 0.8772
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as pyrrolo[2,3-d]pyrimidines. These are aromatic heteropolycyclic compounds containing a pyrrolo[2,3-d]pyrimidine ring system, which is an pyrrolopyrimidine isomers having the 3 ring nitrogen atoms at the 1-, 5-, and 7-positions.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pyrrolopyrimidines
- Sub Class
- Pyrrolo[2,3-d]pyrimidines
- Direct Parent
- Pyrrolo[2,3-d]pyrimidines
- Alternative Parents
- Pyrimidines and pyrimidine derivatives / Pyrroles / Pyrazoles / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- Pyrrolo[2,3-d]pyrimidine / Pyrimidine / Heteroaromatic compound / Pyrrole / Pyrazole / Azole / Azacycle / Nitrile / Carbonitrile / Organic nitrogen compound
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- pyrazoles, nitrile, pyrrolopyrimidine (CHEBI:66919)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Ubiquitin protein ligase binding
- Specific Function
- Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
- Gene Name
- JAK1
- Uniprot ID
- P23458
- Uniprot Name
- Tyrosine-protein kinase JAK1
- Molecular Weight
- 133275.995 Da
References
- Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013]
- Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Sh2 domain binding
- Specific Function
- Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptiv...
- Gene Name
- JAK2
- Uniprot ID
- O60674
- Uniprot Name
- Tyrosine-protein kinase JAK2
- Molecular Weight
- 130672.475 Da
References
- Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013]
- Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804]
Drug created on May 13, 2013 12:21 / Updated on May 21, 2019 12:23