Identification

Name
Baricitinib
Accession Number
DB11817
Type
Small Molecule
Groups
Approved, Investigational
Description

Baricitinib is a selective and reversible Janus kinase 1 (JAK1) and 2 (JAK2) inhibitor. Janus kinases belong to the tyrosine protein kinase family and play an important role in the proinflammatory pathway signalling that is frequently over-activated in autoimmune disorders such as rheumatoid arthritis. By blocking the actions of JAK1/2, baricitinib disrupts the activation of downstream signalling molecules and proinflammatory mediators.

Rheumatoid arthritis is a progressive autoimmune disease commonly associated with discomfort, diasability, and joint damage. Throughout disease progression, the disease may further lead to joint erosions and deformities, causing premature mortality, functional impairment, and reduced quality of life [3]. While there are several disease modifying antirheumatic drugs (DMARDs) available for treatment, patients often experience inadequate threapeutic resposes to these drugs. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects, but also led to preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects [1].

In February 2017, Baricitinib was approved for use in the EU as a second-line oral therapy for moderate to severe active rheumatoid arthritis in adults, either alone or in combination with methotrexate. It is marketed under the trade name Olumiant.

Structure
Thumb
Synonyms
Not Available
External IDs
INCB-028050 / INCB028050 / LY-3009104 / LY3009104
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OlumiantTablet, film coated2 mg/1OralEli Lilly & Co. Ltd.2018-05-31Not applicableUs
Categories
UNII
ISP4442I3Y
CAS number
1187594-09-7
Weight
Average: 371.42
Monoisotopic: 371.116443989
Chemical Formula
C16H17N7O2S
InChI Key
XUZMWHLSFXCVMG-UHFFFAOYSA-N
InChI
InChI=1S/C16H17N7O2S/c1-2-26(24,25)22-9-16(10-22,4-5-17)23-8-12(7-21-23)14-13-3-6-18-15(13)20-11-19-14/h3,6-8,11H,2,4,9-10H2,1H3,(H,18,19,20)
IUPAC Name
2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile
SMILES
CCS(=O)(=O)N1CC(CC#N)(C1)N1C=C(C=N1)C1=C2C=CNC2=NC=N1

Pharmacology

Indication

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs as monotherapy or in combination with methotrexate.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

JAK enzymes are part of the family of tyrosine kinases that constitutively bind to the intracellular domains of cytokine receptors [1] and promote the signalling cascades of cytokines and growth factors involved in haematopoiesis, inflammation and immune function that are also implicated in the pathogenesis of rheumatoid arthritis [2]. Circulating proinflammatory cytokines bind to these cell surface receptors. Upon binding of extracellular cytokines and growth factors, JAKs are phosphorylated and activate signal transducers and activators of transcription (STATs). Through the signalling cascades, inflammatory cytokine and chemokine transcription is induced to form inflammatory mediators including IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ and GM-CSF [2].

Baricitinib selectively and reversibly inhibits JAK1 and JAK2 to modulates their signalling pathways, thereby reducing the phosphorylation and activation of STATs [Label]. In isolated enzyme assays, baricitinib also exhibited an inhibitory effect on other types of JAK enzymes,Tyrosine Kinase 2 and JAK3, at higher concentrations needed for JAK1/2 inhibition.

TargetActionsOrganism
ATyrosine-protein kinase JAK1
inhibitor
Human
ATyrosine-protein kinase JAK2
inhibitor
Human
AProtein-tyrosine kinase 2-beta
inhibitor
Human
ATyrosine-protein kinase JAK3
inhibitor
Human
Absorption

Baricitinib diaplays a dose-proportional increase in systemic exposure in the therapeutic dose range with linear pharmacokinetics. When orally administered, baricitinb is rapidly absorbed with an oral bioavailability of approximately 79 % (CV = 3.94 %). It has a median time to reach peak plasma concentration (Tmax) of 1hour (range: 0.5-3hours). Food consumption affects the exposure by decreasing it by up to 14 %, and decreasing the peak plasma concentration (Cmax) by up to 18 % and Tmax by 0.5 hours [Label].

Volume of distribution

Mean volume of distribution following intravenous infusion administration is 76 L [Label].

Protein binding

Baricitinib is approximately 50 % bound to plasma proteins [Label].

Metabolism

Baricitinib undergoes oxidation by CYP3A4, although less than 10% of the total dose is prone to this biotransformation. There is no formation of quantifiable metabolites in the plasma [Label].

Route of elimination

In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and feces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in feces) constituting approximately 5 % and 1 % of the dose, respectively [Label].

Half life

Mean half-life in patients with rheumatoid arthritis is approximately 12.5 hrs (CV = 27.4 %) [Label].

Clearance

Mean apparent clearance (CL/F) in patients with rheumatoid arthritis is approximately 9.42 L/hr (CV = 34.3 %) [Label].

Toxicity

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Although unknown clinical relevance, bariticinib has shown to decrease the counts in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissues of the immune system in mice, rats and dogs. Opportunistic infections related to demodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure. At doses approximately 6-36 times the indicated doses in humans, decreases in red blood cells was observed in mice, rats and dogs.

In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively). Baricitinib decreased fertility and conception indices in a combined male/female rat fertility study. Decreased overall maing performance was likely due to altered reproductive functions of female rats, as there were no detectable changes on spermatogenesis or semen/sperm endpoints in male rats. In female rats, there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos. In a dog pre- and postnatal development study, there were decreased pup weights at exposure 4 times the human exposure and decreased postnatal survival following exposure 21 times the human exposure. Baricitinib was detected in the milk of lactating rats {FDA Label].

Clinical relevance in humans is not yet established. All the adverse reactions associated with baricitinib are expected to occur dose-dependently.

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

Interactions

Drug Interactions
DrugInteractionDrug group
AcetaminophenThe serum concentration of Baricitinib can be increased when it is combined with Acetaminophen.Approved
Acetyl sulfisoxazoleThe metabolism of Baricitinib can be decreased when combined with Acetyl sulfisoxazole.Approved, Vet Approved
AgmatineThe serum concentration of Agmatine can be increased when it is combined with Baricitinib.Experimental, Investigational
AmiodaroneThe serum concentration of Baricitinib can be increased when it is combined with Amiodarone.Approved, Investigational
AmlodipineThe serum concentration of Baricitinib can be increased when it is combined with Amlodipine.Approved
ApalutamideThe serum concentration of Baricitinib can be decreased when it is combined with Apalutamide.Approved, Investigational
AprepitantThe serum concentration of Baricitinib can be increased when it is combined with Aprepitant.Approved, Investigational
AtazanavirThe metabolism of Baricitinib can be decreased when combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Baricitinib can be decreased when combined with Atomoxetine.Approved
Benzyl alcoholThe serum concentration of Baricitinib can be increased when it is combined with Benzyl alcohol.Approved
BepridilThe serum concentration of Baricitinib can be increased when it is combined with Bepridil.Approved, Withdrawn
BoceprevirThe metabolism of Baricitinib can be decreased when combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Baricitinib can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Baricitinib can be decreased when it is combined with Bosentan.Approved, Investigational
CaffeineThe serum concentration of Baricitinib can be increased when it is combined with Caffeine.Approved
CarbamazepineThe metabolism of Baricitinib can be increased when combined with Carbamazepine.Approved, Investigational
CarvedilolThe serum concentration of Baricitinib can be increased when it is combined with Carvedilol.Approved, Investigational
CeritinibThe serum concentration of Baricitinib can be increased when it is combined with Ceritinib.Approved
CimetidineThe serum concentration of Cimetidine can be increased when it is combined with Baricitinib.Approved, Investigational
ClarithromycinThe metabolism of Baricitinib can be decreased when combined with Clarithromycin.Approved
ClotrimazoleThe metabolism of Baricitinib can be decreased when combined with Clotrimazole.Approved, Vet Approved
CobicistatThe metabolism of Baricitinib can be decreased when combined with Cobicistat.Approved
ConivaptanThe serum concentration of Conivaptan can be increased when it is combined with Baricitinib.Approved, Investigational
CrizotinibThe metabolism of Baricitinib can be decreased when combined with Crizotinib.Approved
CurcuminThe metabolism of Baricitinib can be decreased when combined with Curcumin.Approved, Investigational
CyclosporineThe serum concentration of Baricitinib can be increased when it is combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Baricitinib can be decreased when it is combined with Dabrafenib.Approved, Investigational
DarunavirThe metabolism of Baricitinib can be decreased when combined with Darunavir.Approved
DasatinibThe serum concentration of Baricitinib can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Baricitinib can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Baricitinib can be decreased when combined with Delavirdine.Approved
DexamethasoneThe serum concentration of Baricitinib can be decreased when it is combined with Dexamethasone.Approved, Investigational, Vet Approved
DexniguldipineThe serum concentration of Baricitinib can be increased when it is combined with Dexniguldipine.Experimental
DexverapamilThe serum concentration of Baricitinib can be increased when it is combined with Dexverapamil.Experimental
DihydroergotamineThe metabolism of Baricitinib can be decreased when combined with Dihydroergotamine.Approved, Investigational
DiltiazemThe metabolism of Baricitinib can be decreased when combined with Diltiazem.Approved, Investigational
DoxazosinThe serum concentration of Baricitinib can be increased when it is combined with Doxazosin.Approved
DoxycyclineThe metabolism of Baricitinib can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Baricitinib can be decreased when combined with Dronedarone.Approved
EltrombopagThe serum concentration of Baricitinib can be increased when it is combined with Eltrombopag.Approved
EmopamilThe serum concentration of Baricitinib can be increased when it is combined with Emopamil.Experimental
EnzalutamideThe serum concentration of Baricitinib can be decreased when it is combined with Enzalutamide.Approved
ErythromycinThe metabolism of Baricitinib can be decreased when combined with Erythromycin.Approved, Investigational, Vet Approved
EstradiolThe excretion of Estradiol can be decreased when combined with Baricitinib.Approved, Investigational, Vet Approved
FelodipineThe serum concentration of Baricitinib can be increased when it is combined with Felodipine.Approved, Investigational
FentanylThe serum concentration of Baricitinib can be increased when it is combined with Fentanyl.Approved, Illicit, Investigational, Vet Approved
FluconazoleThe metabolism of Baricitinib can be decreased when combined with Fluconazole.Approved, Investigational
FluoxetineThe serum concentration of Baricitinib can be increased when it is combined with Fluoxetine.Approved, Vet Approved
FluvoxamineThe serum concentration of Baricitinib can be increased when it is combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Baricitinib can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Baricitinib can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Baricitinib can be increased when combined with Fosphenytoin.Approved, Investigational
FurosemideThe excretion of Baricitinib can be decreased when combined with Furosemide.Approved, Vet Approved
Fusidic AcidThe serum concentration of Baricitinib can be increased when it is combined with Fusidic Acid.Approved, Investigational
GallopamilThe serum concentration of Baricitinib can be increased when it is combined with Gallopamil.Investigational
GlyburideThe serum concentration of Glyburide can be increased when it is combined with Baricitinib.Approved
GlycerinThe serum concentration of Baricitinib can be increased when it is combined with Glycerin.Approved, Investigational
HistamineThe serum concentration of Histamine can be increased when it is combined with Baricitinib.Approved, Investigational
IbuprofenThe serum concentration of Baricitinib can be increased when it is combined with Ibuprofen.Approved
IdelalisibThe metabolism of Baricitinib can be decreased when combined with Idelalisib.Approved
ImatinibThe metabolism of Baricitinib can be decreased when combined with Imatinib.Approved
IndinavirThe metabolism of Baricitinib can be decreased when combined with Indinavir.Approved
IrinotecanThe serum concentration of Irinotecan can be increased when it is combined with Baricitinib.Approved, Investigational
IsavuconazoleThe serum concentration of Baricitinib can be increased when it is combined with Isavuconazole.Approved, Investigational
IsavuconazoniumThe metabolism of Baricitinib can be decreased when combined with Isavuconazonium.Approved, Investigational
IsradipineThe serum concentration of Baricitinib can be increased when it is combined with Isradipine.Approved, Investigational
ItraconazoleThe metabolism of Baricitinib can be decreased when combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Baricitinib can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe metabolism of Baricitinib can be decreased when combined with Ketoconazole.Approved, Investigational
LamivudineThe serum concentration of Lamivudine can be increased when it is combined with Baricitinib.Approved, Investigational
LidocaineThe serum concentration of Baricitinib can be increased when it is combined with Lidocaine.Approved, Vet Approved
LomerizineThe serum concentration of Baricitinib can be increased when it is combined with Lomerizine.Experimental
LoperamideThe serum concentration of Baricitinib can be increased when it is combined with Loperamide.Approved
LopinavirThe metabolism of Baricitinib can be decreased when combined with Lopinavir.Approved
LoratadineThe serum concentration of Baricitinib can be increased when it is combined with Loratadine.Approved, Investigational
LorpiprazoleThe serum concentration of Baricitinib can be increased when it is combined with Lorpiprazole.Approved
LosartanThe serum concentration of Baricitinib can be increased when it is combined with Losartan.Approved
LovastatinThe metabolism of Baricitinib can be decreased when combined with Lovastatin.Approved, Investigational
LuliconazoleThe serum concentration of Baricitinib can be increased when it is combined with Luliconazole.Approved
LumacaftorThe serum concentration of Baricitinib can be decreased when it is combined with Lumacaftor.Approved
MetforminThe serum concentration of Metformin can be increased when it is combined with Baricitinib.Approved
MibefradilThe metabolism of Baricitinib can be decreased when combined with Mibefradil.Investigational, Withdrawn
MiconazoleThe serum concentration of Baricitinib can be increased when it is combined with Miconazole.Approved, Investigational, Vet Approved
MifepristoneThe serum concentration of Baricitinib can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Baricitinib can be decreased when it is combined with Mitotane.Approved
NefazodoneThe metabolism of Baricitinib can be decreased when combined with Nefazodone.Approved, Withdrawn
NelfinavirThe metabolism of Baricitinib can be decreased when combined with Nelfinavir.Approved
NetupitantThe serum concentration of Baricitinib can be increased when it is combined with Netupitant.Approved, Investigational
NevirapineThe metabolism of Baricitinib can be increased when combined with Nevirapine.Approved
NicardipineThe serum concentration of Baricitinib can be increased when it is combined with Nicardipine.Approved, Investigational
NiguldipineThe serum concentration of Baricitinib can be increased when it is combined with Niguldipine.Experimental
NilotinibThe metabolism of Baricitinib can be decreased when combined with Nilotinib.Approved, Investigational
NimodipineThe serum concentration of Baricitinib can be increased when it is combined with Nimodipine.Approved, Investigational
NisoldipineThe serum concentration of Baricitinib can be increased when it is combined with Nisoldipine.Approved
NitrendipineThe serum concentration of Baricitinib can be increased when it is combined with Nitrendipine.Approved, Investigational
OlaparibThe metabolism of Baricitinib can be decreased when combined with Olaparib.Approved
OmeprazoleThe serum concentration of Baricitinib can be increased when it is combined with Omeprazole.Approved, Investigational, Vet Approved
OsimertinibThe serum concentration of Baricitinib can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Baricitinib can be increased when it is combined with Palbociclib.Approved, Investigational
ParoxetineThe serum concentration of Baricitinib can be increased when it is combined with Paroxetine.Approved, Investigational
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Baricitinib.Approved
PentobarbitalThe metabolism of Baricitinib can be increased when combined with Pentobarbital.Approved, Investigational, Vet Approved
PhenobarbitalThe metabolism of Baricitinib can be increased when combined with Phenobarbital.Approved, Investigational
PhenytoinThe metabolism of Baricitinib can be increased when combined with Phenytoin.Approved, Vet Approved
PitolisantThe serum concentration of Baricitinib can be decreased when it is combined with Pitolisant.Approved, Investigational
PosaconazoleThe metabolism of Baricitinib can be decreased when combined with Posaconazole.Approved, Investigational, Vet Approved
PramipexoleThe serum concentration of Pramipexole can be increased when it is combined with Baricitinib.Approved, Investigational
PrimidoneThe metabolism of Baricitinib can be increased when combined with Primidone.Approved, Vet Approved
PromethazineThe serum concentration of Baricitinib can be increased when it is combined with Promethazine.Approved, Investigational
PropafenoneThe serum concentration of Baricitinib can be increased when it is combined with Propafenone.Approved
RanitidineThe serum concentration of Baricitinib can be increased when it is combined with Ranitidine.Approved
RanolazineThe serum concentration of Baricitinib can be increased when it is combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Baricitinib can be increased when combined with Rifabutin.Approved, Investigational
RifampicinThe metabolism of Baricitinib can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Baricitinib can be increased when combined with Rifapentine.Approved, Investigational
RolapitantThe serum concentration of Baricitinib can be increased when it is combined with Rolapitant.Approved, Investigational
RucaparibThe metabolism of Baricitinib can be decreased when combined with Rucaparib.Approved, Investigational
SaquinavirThe metabolism of Baricitinib can be decreased when combined with Saquinavir.Approved, Investigational
SarilumabThe therapeutic efficacy of Baricitinib can be decreased when used in combination with Sarilumab.Approved, Investigational
SildenafilThe metabolism of Baricitinib can be decreased when combined with Sildenafil.Approved, Investigational
SiltuximabThe serum concentration of Baricitinib can be decreased when it is combined with Siltuximab.Approved, Investigational
SimeprevirThe serum concentration of Baricitinib can be increased when it is combined with Simeprevir.Approved
St. John's WortThe serum concentration of Baricitinib can be decreased when it is combined with St. John's Wort.Approved, Investigational, Nutraceutical
StiripentolThe serum concentration of Baricitinib can be increased when it is combined with Stiripentol.Approved
SulfisoxazoleThe metabolism of Baricitinib can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe metabolism of Baricitinib can be decreased when combined with Telaprevir.Approved, Withdrawn
TelithromycinThe metabolism of Baricitinib can be decreased when combined with Telithromycin.Approved
TeriflunomideThe serum concentration of Baricitinib can be increased when it is combined with Teriflunomide.Approved
TetracyclineThe excretion of Baricitinib can be decreased when combined with Tetracycline.Approved, Vet Approved
TetrandrineThe serum concentration of Baricitinib can be increased when it is combined with Tetrandrine.Experimental
TiclopidineThe metabolism of Baricitinib can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Baricitinib can be decreased when it is combined with Tocilizumab.Approved
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Baricitinib.Approved, Investigational
VemurafenibThe serum concentration of Baricitinib can be increased when it is combined with Vemurafenib.Approved
VenlafaxineThe serum concentration of Baricitinib can be increased when it is combined with Venlafaxine.Approved
VerapamilThe serum concentration of Baricitinib can be increased when it is combined with Verapamil.Approved
VoriconazoleThe metabolism of Baricitinib can be decreased when combined with Voriconazole.Approved, Investigational
ZidovudineThe serum concentration of Zidovudine can be increased when it is combined with Baricitinib.Approved
ZiprasidoneThe metabolism of Baricitinib can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  1. Kuriya B, Cohen MD, Keystone E: Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential. Ther Adv Musculoskelet Dis. 2017 Feb;9(2):37-44. doi: 10.1177/1759720X16687481. Epub 2017 Jan 23. [PubMed:28255337]
  2. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS: Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247. [PubMed:27028914]
  3. Ni H, Moe S, Myint KT, Htet A: Oral janus kinase inhibitor for the treatment of rheumatoid arthritis: tofacitinib. ISRN Rheumatol. 2013 Jul 21;2013:357904. doi: 10.1155/2013/357904. eCollection 2013. [PubMed:23970975]
  4. O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A: Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013 Apr;72 Suppl 2:ii111-5. doi: 10.1136/annrheumdis-2012-202576. [PubMed:23532440]
External Links
KEGG Drug
D10308
PubChem Compound
44205240
PubChem Substance
347828164
ChemSpider
26373084
BindingDB
50021656
ChEBI
95341
ChEMBL
CHEMBL2105759
HET
3JW
Wikipedia
Baricitinib
PDB Entries
4w9x
FDA label
Download (374 KB)
MSDS
Download (53.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic ScienceHealthy Volunteers13
1CompletedBasic ScienceHepatic Insufficiency / Liver Diseases1
1CompletedTreatmentChronic Inflammatory Disorder / Rheumatoid Arthritis1
1CompletedTreatmentHealthy Volunteers1
1, 2RecruitingTreatmentChronic Graft Versus Host Disease1
2CompletedTreatmentAtopic Dermatitis (AD)1
2CompletedTreatmentDiabetic Kidney Disease1
2CompletedTreatmentPsoriasis / Skin Diseases / Skin Diseases, Papulosquamous1
2CompletedTreatmentRheumatoid Arthritis3
2CompletedTreatmentSystemic Lupus Erythematosus (SLE)1
2RecruitingTreatmentGiant Cells Arteritis1
2, 3Not Yet RecruitingTreatmentAlopecia Areata (AA)1
3Active Not RecruitingTreatmentRheumatoid Arthritis1
3CompletedTreatmentRheumatoid Arthritis5
3Enrolling by InvitationTreatmentAtopic Dermatitis (AD)1
3Not Yet RecruitingTreatmentSystemic Lupus Erythematosus (SLE)2
3RecruitingTreatmentAtopic Dermatitis (AD)5
Not AvailableAvailableNot AvailableAicardi-Goutières Syndrome (AGS) / Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE) / Juvenile Dermatomyositis (JDM) / Stimulator of Interferon Genes (STING)-Associated Vasculopathy With Onset During Infancy (SAVI)1
Not AvailableRecruitingNot AvailableRheumatoid Arthritis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8420629No2009-03-102029-03-10Us
US8158616No2010-06-082030-06-08Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)707.2MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.357 mg/mLALOGPS
logP1.08ALOGPS
logP-0.19ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)13.89ChemAxon
pKa (Strongest Basic)3.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area120.56 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity105.55 m3·mol-1ChemAxon
Polarizability36.72 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

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 / Organosulfonamides / Organic sulfonamides / Sulfonyls / Pyrroles / Pyrazoles / Heteroaromatic compounds / Azetidines / Nitriles / Azacyclic compounds
show 3 more
Substituents
Pyrrolo[2,3-d]pyrimidine / Pyrimidine / Organic sulfonic acid amide / Organosulfonic acid amide / Azole / Pyrazole / Pyrrole / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Sulfonyl
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In isolated enzyme assays, baricitinib inhibited the activities of JAK1 with IC50 value of 5.9nM.
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. Kuriya B, Cohen MD, Keystone E: Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential. Ther Adv Musculoskelet Dis. 2017 Feb;9(2):37-44. doi: 10.1177/1759720X16687481. Epub 2017 Jan 23. [PubMed:28255337]
  2. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS: Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247. [PubMed:27028914]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In isolated enzyme assays, baricitinib inhibited the activities of JAK2 with IC50 value of 5.7nM.
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. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS: Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247. [PubMed:27028914]
  2. Kuriya B, Cohen MD, Keystone E: Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential. Ther Adv Musculoskelet Dis. 2017 Feb;9(2):37-44. doi: 10.1177/1759720X16687481. Epub 2017 Jan 23. [PubMed:28255337]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In isolated enzyme assays, baricitinib inhibited the activities of tyrosine kinase with IC50 value of 53nM.
General Function
Signal transducer activity
Specific Function
Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulat...
Gene Name
PTK2B
Uniprot ID
Q14289
Uniprot Name
Protein-tyrosine kinase 2-beta
Molecular Weight
115873.62 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In isolated enzyme assays, baricitinib inhibited the activities of JAK3 with IC50 value of >400nM.
General Function
Protein tyrosine kinase activity
Specific Function
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a...
Gene Name
JAK3
Uniprot ID
P52333
Uniprot Name
Tyrosine-protein kinase JAK3
Molecular Weight
125097.565 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
In vitro, less than 10% of baricitinib is oxidatively metabolized by CYP3A4 [FDA Label].
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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Coadministration of baricitinib with probenecid, a potent OAT3 inhibitor, resulted in increased AUC with no change in Cmax or Tmax of baricitinib. Concomitant use of OAT3 inhibitors such as diclofenac and ibupprofen may lead to increased exposure of baricitinib, however a clinically relevant interaction is not expected. Methotrexate, a substrate of several transporters including OAT3, is not reported to induce a clinically meaningful effect on baricitinib exposure. The inhibition was observed in vitro.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Inhibition was observed in vitro.
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Inhibition was observed in vitro.
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition was observed in vitro.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition was observed in vitro.
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition was observed in vitro.
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition was observed in vitro.
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition was observed in vitro.
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

Drug created on October 20, 2016 14:50 / Updated on August 02, 2018 06:30