Identification

Name
Filgotinib
Accession Number
DB14845
Description

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
Thumb
Weight
Average: 425.51
Monoisotopic: 425.152160795
Chemical Formula
C21H23N5O3S
Synonyms
Not Available

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

Associated Conditions
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

TargetActionsOrganism
ATyrosine-protein kinase JAK1
inhibitor
Humans
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

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
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Filgotinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Filgotinib.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Filgotinib.
AminophyllineThe serum concentration of Aminophylline can be increased when it is combined with Filgotinib.
AnagrelideThe serum concentration of Anagrelide can be increased when it is combined with Filgotinib.
AsunaprevirThe serum concentration of Asunaprevir can be increased when it is combined with Filgotinib.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Filgotinib.
AxitinibThe serum concentration of Axitinib can be increased when it is combined with Filgotinib.
BendamustineThe serum concentration of Bendamustine can be increased when it is combined with Filgotinib.
BenzylpenicillinThe serum concentration of Benzylpenicillin can be increased when it is combined with Filgotinib.
Additional Data Available
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  • Severity
    Severity
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Filgotinib maleateJG8OB4UL9Y1802998-75-9BFENHEAPFWQJFL-BTJKTKAUSA-N

Categories

Drug Categories
Classification
Not classified

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
  1. 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. [PubMed:29461286]
  2. 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. [PubMed:31912462]
  3. 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. [PubMed:31692920]
  4. Wasserman AM: Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011 Dec 1;84(11):1245-52. [PubMed:22150658]
  5. 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. [PubMed:29736302]
  6. 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. [PubMed:29942363]
  7. 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. [PubMed:28441353]
  8. 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. [PubMed:26482170]
  9. 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. [PubMed:25681059]
  10. EMA Label - Jyseleca (filgotinib) [Link]
ChemSpider
28189566
BindingDB
103727
ChEMBL
CHEMBL3301607
ZINC
ZINC000096174616
PDBe Ligand
2HB
Wikipedia
Filgotinib
PDB Entries
4p7e / 5ut5

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentNovel Coronavirus Infectious Disease (COVID-19) / Psoriatic Arthritis1
3Active Not RecruitingTreatmentPsoriatic Arthritis1
3Active Not RecruitingTreatmentRheumatoid Arthritis1
3Active Not RecruitingTreatmentUlcerative Colitis1
3CompletedTreatmentRheumatoid Arthritis3
3CompletedTreatmentUlcerative Colitis1
3Enrolling by InvitationTreatmentCrohn's Disease (CD)1
3Not Yet RecruitingTreatmentAnkylosing Spondylitis (AS)2
3RecruitingTreatmentCrohn's Disease (CD)1
2Active Not RecruitingTreatmentAnkylosing Spondylitis (AS) / Non-Radiographical Axial Spondyloarthritis / Psoriatic Arthritis / Rheumatoid Arthritis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.177 mg/mLALOGPS
logP1.99ALOGPS
logP2.03ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)10.96ChemAxon
pKa (Strongest Basic)3.32ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area96.67 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity126.12 m3·mol-1ChemAxon
Polarizability44.72 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

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
  1. 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. [PubMed:31912462]

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
  1. 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. [PubMed:26482170]
  2. 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. [PubMed:25681059]
  3. 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. [PubMed:30088677]
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
  1. 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. [PubMed:26482170]
  2. 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. [PubMed:25681059]

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
  1. EMA Label - Jyseleca (filgotinib) [Link]

Drug created on May 20, 2019 08:30 / Updated on October 19, 2020 02:19

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