Baricitinib

Identification

Name

Baricitinib

Accession Number

DB11817

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 the EU, baricitinib was approved in February of 2017 as a second-line orally administered treatment for moderate to severe active rheumatoid arthritis in adults, either as a monotherapy or when combined with methotrexate. It is marketed under the trade name Olumiant.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Baricitinib (DB11817)

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Weight

Average: 371.42
Monoisotopic: 371.116443989

Chemical Formula

C₁₆H₁₇N₇O₂S

Synonyms

• Baricitinib

External IDs

• INCB-028050
• INCB028050
• LY-3009104
• LY3009104

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

• Moderate, active Rheumatoid arthritis
• Severe, active Rheumatoid arthritis

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
ATyrosine-protein kinase JAK1	inhibitor	Humans
ATyrosine-protein kinase JAK2	inhibitor	Humans
AProtein-tyrosine kinase 2-beta	inhibitor	Humans
ATyrosine-protein kinase JAK3	inhibitor	Humans

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.

Adverse Effects

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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

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Baricitinib which could result in a higher serum level.
Abametapir	The serum concentration of Baricitinib can be increased when it is combined with Abametapir.
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Baricitinib.
Abemaciclib	The excretion of Baricitinib can be decreased when combined with Abemaciclib.
Acarbose	Acarbose may decrease the excretion rate of Baricitinib which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Baricitinib which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Baricitinib which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Baricitinib which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Baricitinib which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Baricitinib which could result in a higher serum level.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Take at the same time every day.
• Take with or without food.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Olumiant	Tablet, film coated	1 mg/1	Oral	Eli Lilly and Company	2019-10-08	Not applicable
Olumiant	Tablet, film coated	2 mg/1	Oral	Eli Lilly and Company	2018-05-31	Not applicable
Olumiant	Tablet	2 mg	Oral	Eli Lilly & Co. Ltd.	2018-09-27	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L04AA37 — Baricitinib

• L04AA — Selective immunosuppressants
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amides
• Antineoplastic and Immunomodulating Agents
• Azetines
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Immunosuppressive Agents
• Janus Kinase Inhibitor
• Janus Kinase Inhibitors
• MATE 2 Inhibitors
• MATE 2 Substrates
• MATE 2 Substrates with a Narrow Therapeutic Index
• MATE inhibitors
• MATE substrates
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• OAT3/SLC22A8 Substrates
• OATP1B3 inhibitors
• OCT2 Inhibitors
• P-glycoprotein substrates
• Selective Immunosuppressants
• Sulfones
• Sulfur Compounds

Chemical TaxonomyProvided by Classyfire

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 / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives

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Substituents

Aromatic heteropolycyclic compound / Azacycle / Azetidine / Azole / Carbonitrile / Heteroaromatic compound / Hydrocarbon derivative / Nitrile / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organic sulfonic acid amide / Organic sulfonic acid or derivatives / Organonitrogen compound / Organopnictogen compound / Organosulfonic acid amide / Organosulfonic acid or derivatives / Organosulfur compound / Pyrazole / Pyrimidine / Pyrrole / Pyrrolo[2,3-d]pyrimidine / Sulfonyl

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

ISP4442I3Y

CAS number

1187594-09-7

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

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

RxNav

2047232

ChEBI

95341

ChEMBL

CHEMBL2105759

ZINC

ZINC000073069247

PDBe Ligand

3JW

Wikipedia

Baricitinib

AHFS Codes

• 92:44.00 — Immunosuppressive Agents

PDB Entries

4w9x

FDA label

Download (374 KB)

MSDS

Download (53.8 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Novel Coronavirus Infectious Disease (COVID-19)	1
4	Recruiting	Treatment	Rheumatoid Arthritis	2
3	Active Not Recruiting	Treatment	Alopecia Areata (AA)	1
3	Active Not Recruiting	Treatment	Atopic Dermatitis (AD)	3
3	Active Not Recruiting	Treatment	Novel Coronavirus Infectious Disease (COVID-19)	1
3	Active Not Recruiting	Treatment	Rheumatoid Arthritis	1
3	Active Not Recruiting	Treatment	Systemic Lupus Erythematosus (SLE)	2
3	Completed	Treatment	Atopic Dermatitis (AD)	3
3	Completed	Treatment	Rheumatoid Arthritis	5
3	Enrolling by Invitation	Treatment	Atopic Dermatitis (AD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	2 mg
Tablet, coated	Oral	2 mg
Tablet, coated	Oral	4 mg
Tablet, film coated	Oral	1 mg/1
Tablet, film coated	Oral	2 MG
Tablet, film coated	Oral	2 mg/1
Tablet, film coated	Oral	4 MG
Tablet
Tablet, coated		2 mg
Tablet, coated		4 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US8420629	No	2013-04-16	2029-03-10
US8158616	No	2012-04-17	2030-06-08

Additional Data Available

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

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	707.2	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.357 mg/mL	ALOGPS
logP	1.08	ALOGPS
logP	-0.19	ChemAxon
logS	-3	ALOGPS
pKa (Strongest Acidic)	13.89	ChemAxon
pKa (Strongest Basic)	3.91	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	120.56 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	105.55 m3·mol-1	ChemAxon
Polarizability	36.72 Å3	ChemAxon
Number of Rings	4	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, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on October 20, 2016 14:50 / Updated on October 27, 2020 11:13