Filgotinib
Identification
- Summary
Filgotinib is a Janus kinase (JAK) 1 selective inhibitor used to treat cases of rheumatoid arthritis that are unresponsive to conventional treatments.
- Generic Name
- Filgotinib
- DrugBank Accession Number
- DB14845
- Background
Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, and inflammatory disease that causes synovial joint symptoms and can limit range of motion in severe cases.4,5 The disease is associated with extra-articular manifestations, progressive disability, and comorbidities including cardiovascular disease and mental disorders.3 50-70% of patients with RA are unable to achieve sustained clinical remission despite the availability of several treatments including disease-modifying anti-rheumatic drugs (DMARDS) like methotrexate, interleukin-6 (IL-6) blockers, and tumor necrosis factor (TNF) inhibitors.3 New therapeutic developments target other inflammatory pathways implicated in RA including the Janus kinase (JAK) signaling pathway as seen with filgotinib.5
There are four JAK subtypes which include JAK1, JAK2, JAK3, and tyrosine kinase 2.3 Non-selective JAK inhibitors like tofacitinib target JAK1 and JAK3 subtypes with minimal activity at JAK2. In contrast, the newly approved filgotinib is a highly selective JAK1 inhibitor.3 JAK2 and JAK3 play important roles in both immune and hematologic functions; therefore, selectivity for JAK1 aims to improve the safety profile of filgotinib while maintaining clinical efficacy.3 Filgotinib is currently reserved for patients who cannot tolerate DMARDs, or who have been unable to achieve remission in response to one or more DMARDs.10
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 425.51
Monoisotopic: 425.152160795 - Chemical Formula
- C21H23N5O3S
- Synonyms
- Filgotinib
Pharmacology
- Indication
Filgotinib is indicated for the treatment of active moderate to severe rheumatoid arthritis alone or in combination with methotrexate.10 Filgotinib is currently reserved for patients who are unable to tolerate or who have not responded adequately to one or more disease-modifying anti-rheumatic drugs (DMARDS).10
Filgotinib is also indicated for treatment of moderately to severely active ulcerative colitis in adult patients who had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic agent.11
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Active, moderate to severe rheumatoid arthritis •••••••••••• ••••• •••••••••• •••••••• •• ••••••••••• •• •••••• ••••••• •••• •••••• Used in combination to treat Active, moderate to severe rheumatoid arthritis Regimen in combination with: Methotrexate (DB00563) •••••••••••• ••••• •••••••••• •••••••• •• ••••••••••• •• •••••• ••••••• •••• •••••• Treatment of Moderately to severely active ulcerative colitis •••••••••••• ••••• •••••••••• •••••••• ••••• •••• •••••••• ••• •• •••• •••••••••• •• •••••• •••••••••••• ••••••• •• • •••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
In addition to targeted Janus kinase (JAK) 1 inhibition, filgotinib targets pro-inflammatory cytokine signalling by inhibiting IL-6 induced STAT1 phosphorylation.3,10 Serum C-reactive protein levels are also reduced in response to filgotinib administration.10
- Mechanism of action
There are four Janus kinase (JAK) enzymes including JAK1, JAK2, JAK3, and tyrosine kinase 2.3 JAK1 mediates inflammatory cytokine signaling, while JAK2 and JAK3 are important components of hematologic and immune functions.3,10 Filgotinib selectively inhibits JAK1 and is for example nearly 30-fold more selective for JAK1 compared to JAK2.3,10
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is implicated in several inflammatory pathologies and has been found to be continuously active in patients who have RA.6 Sustained activation of this pathway contributes to aberrant processes which lead to disease progression including elevated levels of matrix metalloproteinases (MMPs) and reduced cell apoptosis in RA affected synovial tissues.6 Filgotinib acts on the JAK-STAT pathway by selectively inhibiting JAK1 phosphorylation and preventing STAT activation, which ultimately results in reduced proinflammatory cytokine signaling.3
Target Actions Organism ATyrosine-protein kinase JAK1 inhibitorHumans - Absorption
Filgotinib is rapidly absorbed after oral administration.10 Median peak plasma concentrations occurred 2-3 hours post-dose for filgotinib and 5 hours post-dose for GS-829845.10 Steady-state concentrations can be observed in 2-3 days for filgotinib and in 4 days for GS-829845.10 Food does not appear to have a significant effect on the absorption of filgotinib; therefore, the medication can be administered without regard to food.10
After repeated oral dosing of filgotinib 200 mg, the reported Cmax and AUCτ values of filgotinib were 2.15 ug/mL and 6.77 ugxh/mL, respectively.10 For GS-829845 (the major metabolite) the reported Cmax was 4.43 ug/mL and the reported AUCτ was 83.2 ugxh/mL.10
- Volume of distribution
Not Available
- Protein binding
Approximately 55-59% of filgotinib is protein-bound, while 39-44% of the active metabolite GS-829845 is protein-bound.10
- Metabolism
Carboxylesterase enzymes are involved in the metabolism of filgotinib.8 The carboxylesterase 2 (CES2) isoform is chiefly responsible for metabolizing filgotinib to its major metabolite, GS-829845.8,9 Although carboxylesterase 1 (CES1) plays a less prominent role in the biotransformation of filgotinib, in vitro studies have demonstrated that CES1 will partially compensate in the event of CES2 saturation.8 GS-829845 is thus far the only major circulating metabolite to have been identified.10
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- Route of elimination
Of the total administered dose of filgotinib, approximately 87% undergoes renal elimination while 15% undergoes faecal elimination.10
- Half-life
The half-life of filgotinib is estimated to be 7 hours, while the half-life of its active metabolite GS-829845 is estimated to be 19 hours.10
- Clearance
Not Available
- Adverse Effects
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- Toxicity
Toxicity information regarding filgotinib is not readily available; however, it has been administered in clinical trials at doses of up to 450 mg daily.10 Associated adverse effects were similar to those observed at lower doses.10 In the event of overdose, the patient should be closely monitored and supportive measures should be initiated as required.10
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Filgotinib. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Filgotinib. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Filgotinib. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Filgotinib. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Filgotinib. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Filgotinib maleate JG8OB4UL9Y 1802998-75-9 BFENHEAPFWQJFL-BTJKTKAUSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Jyseleca Tablet, film coated 200 mg Oral Gilead Sciences Ireland Uc, Galapagos Nv 2020-12-16 Not applicable EU Jyseleca Tablet, film coated 100 mg Oral Gilead Sciences Ireland Uc, Galapagos Nv 2020-12-16 Not applicable EU Jyseleca Tablet, film coated 200 mg Oral Gilead Sciences Ireland Uc, Galapagos Nv 2020-12-16 Not applicable EU Jyseleca Tablet, film coated 100 mg Oral Gilead Sciences Ireland Uc, Galapagos Nv 2020-12-16 Not applicable EU
Categories
- ATC Codes
- L04AA45 — Filgotinib
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 3XVL385Q0M
- CAS number
- 1206161-97-8
- InChI Key
- RIJLVEAXPNLDTC-UHFFFAOYSA-N
- InChI
- InChI=1S/C21H23N5O3S/c27-20(17-8-9-17)23-21-22-19-3-1-2-18(26(19)24-21)16-6-4-15(5-7-16)14-25-10-12-30(28,29)13-11-25/h1-7,17H,8-14H2,(H,23,24,27)
- IUPAC Name
- N-(5-{4-[(1,1-dioxo-1lambda6-thiomorpholin-4-yl)methyl]phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
- SMILES
- O=C(NC1=NN2C(C=CC=C2C2=CC=C(CN3CCS(=O)(=O)CC3)C=C2)=N1)C1CC1
References
- General References
- Mahajan TD, Mikuls TR: Recent advances in the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2018 May;30(3):231-237. doi: 10.1097/BOR.0000000000000496. [Article]
- Tarrant JM, Galien R, Li W, Goyal L, Pan Y, Hawtin R, Zhang W, Van der Aa A, Taylor PC: Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials. Rheumatol Ther. 2020 Mar;7(1):173-190. doi: 10.1007/s40744-019-00192-5. Epub 2020 Jan 7. [Article]
- Biggioggero M, Becciolini A, Crotti C, Agape E, Favalli EG: Upadacitinib and filgotinib: the role of JAK1 selective inhibition in the treatment of rheumatoid arthritis. Drugs Context. 2019 Oct 24;8:212595. doi: 10.7573/dic.212595. eCollection 2019. [Article]
- Wasserman AM: Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011 Dec 1;84(11):1245-52. [Article]
- Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J: Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018 Apr 27;6:15. doi: 10.1038/s41413-018-0016-9. eCollection 2018. [Article]
- Malemud CJ: The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018 Jun;10(5-6):117-127. doi: 10.1177/1759720X18776224. Epub 2018 May 19. [Article]
- Araki Y, Mimura T: Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. Int J Mol Sci. 2017 Apr 25;18(5). pii: ijms18050905. doi: 10.3390/ijms18050905. [Article]
- Namour F: Author's Reply to Srinivas: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". Clin Pharmacokinet. 2015 Dec;54(12):1297-8. doi: 10.1007/s40262-015-0336-5. [Article]
- Namour F, Diderichsen PM, Cox E, Vayssiere B, Van der Aa A, Tasset C, Van't Klooster G: Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection. Clin Pharmacokinet. 2015 Aug;54(8):859-74. doi: 10.1007/s40262-015-0240-z. [Article]
- EMA Summary of Product Characteristics: Jyseleca (filgotinib) film-coated tablets for oral use [Link]
- EMA Summary of opinion (post authorisation): Jyseleca (filgotinib) [Link]
- GlobeNewswire: Jyseleca®▼(filgotinib) approved in the European Union for the treatment of ulcerative colitis [Link]
- External Links
- ChemSpider
- 28189566
- BindingDB
- 103727
- ChEMBL
- CHEMBL3301607
- ZINC
- ZINC000096174616
- PDBe Ligand
- 2HB
- Wikipedia
- Filgotinib
- PDB Entries
- 4p7e / 5ut5
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Not Yet Recruiting Treatment Rheumatoid Arthritis 1 4 Recruiting Treatment Rheumatoid Arthritis 1 3 Active Not Recruiting Treatment Rheumatoid Arthritis 1 3 Active Not Recruiting Treatment Ulcerative Colitis 1 3 Completed Treatment Crohn's Disease (CD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 100 MG Tablet, film coated Oral 200 MG - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.177 mg/mL ALOGPS logP 1.99 ALOGPS logP 2.03 Chemaxon logS -3.4 ALOGPS pKa (Strongest Acidic) 10.96 Chemaxon pKa (Strongest Basic) 3.32 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 96.67 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 126.12 m3·mol-1 Chemaxon Polarizability 44.72 Å3 Chemaxon Number of Rings 5 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00si-9302700000-404837ff704eed3ef1a2 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-a0dadce74fa607cd5c3e Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00b9-0009800000-bd081cc666ff2478cf68 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-2009300000-6153f7f70a80de951663 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0gvo-0789200000-f72cf6e35165f3b1e993 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001l-4519100000-ce00517ea730b7303b2b Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 229.9712125 predictedDarkChem Lite v0.1.0 [M+H]+ 230.4238125 predictedDarkChem Lite v0.1.0
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
- Tarrant JM, Galien R, Li W, Goyal L, Pan Y, Hawtin R, Zhang W, Van der Aa A, Taylor PC: Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials. Rheumatol Ther. 2020 Mar;7(1):173-190. doi: 10.1007/s40744-019-00192-5. Epub 2020 Jan 7. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Metabolizer
- Curator comments
- CES2 is largely responsible for the biotransformation of filgotinib to its active metabolite.
- General Function
- Methylumbelliferyl-acetate deacetylase activity
- Specific Function
- Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and ...
- Gene Name
- CES2
- Uniprot ID
- O00748
- Uniprot Name
- Cocaine esterase
- Molecular Weight
- 61806.41 Da
References
- Namour F: Author's Reply to Srinivas: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". Clin Pharmacokinet. 2015 Dec;54(12):1297-8. doi: 10.1007/s40262-015-0336-5. [Article]
- Namour F, Diderichsen PM, Cox E, Vayssiere B, Van der Aa A, Tasset C, Van't Klooster G: Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection. Clin Pharmacokinet. 2015 Aug;54(8):859-74. doi: 10.1007/s40262-015-0240-z. [Article]
- Namour F, Fagard L, Van der Aa A, Harrison P, Xin Y, Tasset C: Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor. Br J Clin Pharmacol. 2018 Dec;84(12):2779-2789. doi: 10.1111/bcp.13726. Epub 2018 Oct 4. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Metabolizer
- General Function
- Triglyceride lipase activity
- Specific Function
- Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
- Gene Name
- CES1
- Uniprot ID
- P23141
- Uniprot Name
- Liver carboxylesterase 1
- Molecular Weight
- 62520.62 Da
References
- Namour F: Author's Reply to Srinivas: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". Clin Pharmacokinet. 2015 Dec;54(12):1297-8. doi: 10.1007/s40262-015-0336-5. [Article]
- Namour F, Diderichsen PM, Cox E, Vayssiere B, Van der Aa A, Tasset C, Van't Klooster G: Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection. Clin Pharmacokinet. 2015 Aug;54(8):859-74. doi: 10.1007/s40262-015-0240-z. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- EMA Summary of Product Characteristics: Jyseleca (filgotinib) film-coated tablets for oral use [Link]
Drug created at May 20, 2019 14:30 / Updated at November 21, 2021 16:21