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
DrugInteraction
AcetaminophenThe serum concentration of Baricitinib can be increased when it is combined with Acetaminophen.
AcetazolamideThe metabolism of Baricitinib can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Baricitinib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Baricitinib which could result in a higher serum level.
AcyclovirThe excretion of Baricitinib can be decreased when combined with Acyclovir.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Baricitinib which could result in a higher serum level.
AgmatineThe serum concentration of Agmatine can be increased when it is combined with Baricitinib.
AlbendazoleThe serum concentration of Baricitinib can be increased when it is combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Baricitinib.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Baricitinib.
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, 3RecruitingTreatmentAlopecia Areata (AA)1
3Active Not RecruitingOtherBone Density / Finger Joints / Rheumatoid Arthritis1
3Active Not RecruitingTreatmentAtopic Dermatitis (AD)1
3Active Not RecruitingTreatmentRheumatoid Arthritis1
3CompletedTreatmentRheumatoid Arthritis5
3Enrolling by InvitationTreatmentAtopic Dermatitis (AD)1
3RecruitingTreatmentAtopic Dermatitis (AD)4
3RecruitingTreatmentSystemic Lupus Erythematosus (SLE)2
Not AvailableNo Longer AvailableNot 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
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, however, the FDA label states that this is unlikely to result in clinically significant drug interactions.
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. Posada MM, Cannady EA, Payne CD, Zhang X, Bacon JA, Pak YA, Higgins JW, Shahri N, Hall SD, Hillgren KM: Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib. Clin Transl Sci. 2017 Nov;10(6):509-519. doi: 10.1111/cts.12486. Epub 2017 Jul 27. [PubMed:28749581]
  2. Baracitinib FDA label [File]
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

Drug created on October 20, 2016 14:50 / Updated on October 10, 2018 14:16