Identification

Name
Fedratinib
Accession Number
DB12500
Description

Fedratinib, also known as SAR302503 and TG101348, is a tyrosine kinase inhibitor used to treat intermediate-2 and high risk primary and secondary myelofibrosis.2,7 It is an anilinopyrimidine derivative.6

Fedratinib was granted FDA approval on August 16, 2019.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 524.678
Monoisotopic: 524.256959738
Chemical Formula
C27H36N6O3S
Synonyms
  • Fedratinib
External IDs
  • SAR 302503
  • SAR-302503
  • SAR302503
  • TG-101348
  • TG101348

Pharmacology

Indication

Fedratinib is indicated to treat adults with primary or secondary myelofibrosis that is either intermediate-2 or high risk.7

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Fedratinib is a kinase inhibitor that inhibits cell division and induces apoptosis.7 Patients taking fedratinib may experience anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, or elevated amylase and lipase.7 These effects should be managed by reducing the dose, temporarily stopping the medication, or providing transfusions on a case by case basis.7

Mechanism of action

Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3.1,7 JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis.7 Fedratinib's inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis.4,7

TargetActionsOrganism
ATyrosine-protein kinase JAK2
inhibitor
Humans
AReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
NTyrosine-protein kinase JAK1
inhibitor
Humans
Absorption

A 400mg oral dose results in a Cmax of 1804ng/mL and an AUC of 26,870ng/*hr/mL.7 Fedratinib has a Tmax of 1.75-3 hours.4,7 A high fat breakfast does not significantly affect the absorption of fedratinib.3

Volume of distribution

The apparent volume of distribution is 1770L.7

Protein binding

Fedratinib is ≥92% protein bound in plasma.7

Metabolism

Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3.7 Beyond that, data regarding the metabolism of fedratinib is not readily available.

Route of elimination

An oral dose of fedratinib is 77% eliminated in the feces with 23% as unchanged drug.7 5% is eliminated in the urine, with 3% as unchanged drug.7

Half-life

The half life of fedratinib is 41 hours with a terminal half life of 114 hours.7

Clearance

The clearance of fedratinib is 13L/h.7

Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

Data regarding fedratinib in overdose is not readily available.7 Patients given 680mg/day experienced a greater incidence and severity of adverse effects including anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and elevated amylase and lipase.5 These effects were treated symptomatically as well as by reducing the dose or temporarily stopping fedratinib.5,7

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Fedratinib.
AbametapirThe serum concentration of Fedratinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Fedratinib can be increased when combined with Abatacept.
AbemaciclibThe excretion of Abemaciclib can be decreased when combined with Fedratinib.
AbirateroneThe metabolism of Fedratinib can be decreased when combined with Abiraterone.
AcenocoumarolThe metabolism of Fedratinib can be decreased when combined with Acenocoumarol.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Fedratinib.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Fedratinib.
AdalimumabThe metabolism of Fedratinib can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Fedratinib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of fedratinib. Dose reduction may be necessary.
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of fedratinib and may reduce its serum concentration.
  • Take with or without food. Food may help reduce adverse effects of fedratinib such as nausea and vomiting.

Products

Product Ingredients
IngredientUNIICASInChI Key
Fedratinib hydrochlorideUH9J2HBQWJ1374744-69-0QAFZLTVOFJHYDF-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
InrebicCapsule100 mgOralCelgeneNot applicableNot applicableCanada flag
InrebicCapsule100 mg/1OralCelgene Corporation2019-08-16Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE57 — Fedratinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzenesulfonamides. These are organic compounds containing a sulfonamide group that is S-linked to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Benzenesulfonamides
Alternative Parents
Benzenesulfonyl compounds / Phenoxy compounds / Phenol ethers / Aniline and substituted anilines / Alkyl aryl ethers / Aminopyrimidines and derivatives / Organosulfonamides / Imidolactams / N-alkylpyrrolidines / Heteroaromatic compounds
show 7 more
Substituents
Alkyl aryl ether / Amine / Aminopyrimidine / Aminosulfonyl compound / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Azacycle / Benzenesulfonamide / Benzenesulfonyl group / Ether
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
6L1XP550I6
CAS number
936091-26-8
InChI Key
JOOXLOJCABQBSG-UHFFFAOYSA-N
InChI
InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)
IUPAC Name
N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide
SMILES
CC1=CN=C(NC2=CC=C(OCCN3CCCC3)C=C2)N=C1NC1=CC=CC(=C1)S(=O)(=O)NC(C)(C)C

References

General References
  1. Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A: Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2015 Aug;1(5):643-51. doi: 10.1001/jamaoncol.2015.1590. [PubMed:26181658]
  2. Jamieson C, Hasserjian R, Gotlib J, Cortes J, Stone R, Talpaz M, Thiele J, Rodig S, Pozdnyakova O: Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis. J Transl Med. 2015 Sep 10;13:294. doi: 10.1186/s12967-015-0644-4. [PubMed:26357842]
  3. Zhang M, Xu C, Ma L, Shamiyeh E, Yin J, von Moltke LL, Smith WB: Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteers. Clin Pharmacol Drug Dev. 2015 Jul;4(4):315-21. doi: 10.1002/cpdd.161. Epub 2014 Oct 27. [PubMed:27136912]
  4. Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL, Smith WB: A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol. 2014 Apr;54(4):415-21. doi: 10.1002/jcph.218. Epub 2013 Nov 16. [PubMed:24165976]
  5. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A: Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789-96. doi: 10.1200/JCO.2010.32.8021. Epub 2011 Jan 10. [PubMed:21220608]
  6. Roskoski R Jr: Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016 Sep;111:784-803. doi: 10.1016/j.phrs.2016.07.038. Epub 2016 Jul 26. [PubMed:27473820]
  7. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
PubChem Compound
16722836
PubChem Substance
347828733
ChemSpider
17626393
BindingDB
50332294
RxNav
2197490
ChEBI
91408
ChEMBL
CHEMBL1287853
ZINC
ZINC000019862646
PDBe Ligand
2TA
Wikipedia
Fedratinib
PDB Entries
4ogj / 4ps5

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHematopoietic Neoplasms1
3RecruitingTreatmentAgnogenic Myeloid Metaplasia / Post-Polycythaemia Vera / Primary Myelofibrosis2
2CompletedTreatmentAgnogenic Myeloid Metaplasia1
2CompletedTreatmentHematopoietic Neoplasms3
2Not Yet RecruitingTreatmentPrimary Myelofibrosis / Secondary Myelofibrosis1
2RecruitingTreatmentAcute Myeloid Leukemia (AML) / Essential Thrombocythemia (ET) / Myelodysplastic Syndrome / Myelodysplastic/Myeloproliferative Neoplasms / Myeloproliferative Neoplasm, Unclassifiable / Myeloproliferative Neoplasms / Polycythemia Vera (PV) / Primary Myelofibrosis / Secondary Myelofibrosis1
1CompletedBasic ScienceNeoplasms Malignant1
1CompletedTreatmentAgnogenic Myeloid Metaplasia1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentHepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg
CapsuleOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10391094No2019-08-272032-05-29US flag
US8138199No2012-03-202028-06-30US flag
US7528143No2009-05-052026-12-16US flag
US7825246No2010-11-022026-12-16US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility4µg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00949 mg/mLALOGPS
logP4.27ALOGPS
logP4.64ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)10.21ChemAxon
pKa (Strongest Basic)9ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area108.48 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity147.88 m3·mol-1ChemAxon
Polarizability57.16 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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
  1. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A: Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011 Mar 1;29(7):789-96. doi: 10.1200/JCO.2010.32.8021. Epub 2011 Jan 10. [PubMed:21220608]
  2. Roskoski R Jr: Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016 Sep;111:784-803. doi: 10.1016/j.phrs.2016.07.038. Epub 2016 Jul 26. [PubMed:27473820]
  3. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
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
  1. Roskoski R Jr: Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016 Sep;111:784-803. doi: 10.1016/j.phrs.2016.07.038. Epub 2016 Jul 26. [PubMed:27473820]

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
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding
Specific Function
Transcription factor that specifically binds to the octamer motif (5'-ATTTGCAT-3'). Regulates transcription in a number of tissues in addition to activating immunoglobulin gene expression. Modulate...
Gene Name
POU2F2
Uniprot ID
P09086
Uniprot Name
POU domain, class 2, transcription factor 2
Molecular Weight
51208.51 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Fedratinib Oral Capsules [Link]

Drug created on October 20, 2016 16:38 / Updated on September 03, 2020 17:44

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