Baricitinib

Clinical data
Trade names	Olumiant
Synonyms	INCB28050, LY3009104
License data	EU EMA: by INN
Routes of administration	By mouth (tablets)
ATC code	L04AA37 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	79%
Protein binding	50%
Metabolism	CYP3A4 (<10%)
Elimination half-life	12.5 hours
Excretion	75% urine, 20% faeces
Identifiers
IUPAC name 2-[1-Ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile
CAS Number	1187594-09-7
PubChem CID	44205240
ChemSpider	26373084
UNII	ISP4442I3Y
KEGG	D10308
ChEMBL	CHEMBL2105759
PDB ligand	3JW (PDBe, RCSB PDB)
ECHA InfoCard	100.219.080
Chemical and physical data
Formula	C16H17N7O2S
Molar mass	371.42 g/mol
3D model (JSmol)	Interactive image
SMILES CCS(=O)(=O)N1CC(C1)(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
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) Key:XUZMWHLSFXCVMG-UHFFFAOYSA-N

Baricitinib (trade name Olumiant) is a drug for the treatment of rheumatoid arthritis (RA), being developed by Incyte and Eli Lilly.^[1] It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.^[2] The drug is approved in Europe.^[3]

Approvals and indications[edit]

In February 2017 Baricitinib was approved for use in the EU as a second-line therapy for moderate to severe active rheumatoid arthritis in adults, either alone or in combination with methotrexate.^[4]

Baricitinib received a CRL from the FDA in April, 2017. The letter indicated that the FDA was unable to approve the application in its current form. Specifically, the FDA indicated that additional clinical data are needed to determine the most appropriate doses and that additional data is necessary to further characterize safety concerns across treatment arms.

On 23 April, 2018, an FDA Advisory Committee recommended approval of baricitinib 2mg for the treatment of rheumatoid arthritis but did not recommend the 4mg dose, citing serious adverse events.^[5] On 31 May 2018 FDA approved Barictinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.^[6]

Contraindications[edit]

During pregnancy, the use of baricitinib is contraindicated.^[4]

Side effects[edit]

In studies, upper respiratory tract infections and high blood cholesterol levels (hypercholesterolemia) occurred in more than 10% of patients. Less common side effects included other infections such as herpes zoster, herpes simplex, urinary tract infections, and gastroenteritis.^[4]

Interactions[edit]

Being metabolised only to a small extent, the substance has a low potential for interactions. In studies, inhibitors of the liver enzymes CYP3A4, CYP2C19 and CYP2C9, as well as the CYP3A4 inducer rifampicin, had no relevant influence on baricitinib concentrations in the bloodstream. While it blocks a number of transporter proteins in vitro, clinically relevant interactions via this mechanism are considered very unlikely, except perhaps for the cation transporter SLC22A1 (OCT1).^[4]

An additive effect with other immunosuppressants cannot be excluded.^[4]

Pharmacology[edit]

Mechanism of action[edit]

Baricitinib reversibly inhibits Janus kinase 1 with a half maximal inhibitory concentration (IC₅₀) of 5.9 nM and Janus kinase 2 with an IC₅₀ of 5.7 nM. Tyrosine kinase 2, which belongs to the same enzyme family, is affected less (IC₅₀ = 53 nM), and Janus kinase 3 even much less (IC₅₀ > 400 nM). Via a signal transduction pathway involving STAT proteins, this ultimately modulates gene expression in immunological cells.^[4]

Pharmacokinetics[edit]

The substance is quickly absorbed from the gut with an absolute bioavailability of 79%. It reaches highest blood plasma levels after about an hour, in different individuals ranging from 0.5 to 3 hours. Food intake has no relevant influence on the drug's pharmacokinetics. 50% of the circulating baricitinib are bound to blood plasma proteins.^[4]

Less than 10% of the substance is metabolised to four different oxidation products by CYP3A4; the rest is left unchanged. Elimination half-life is 12.5 hours on average. About 75% is eliminated via the urine, and 20% via the faeces.^[4]

History[edit]

Clinical trials[edit]

As of August 2016^[update] 31 clinical trials had been registered for baricitinib of which 24 had completed,^[7] and 4 of 6 phase 3 trials had completed.^[8]

This section needs expansion. You can help by adding to it. (April 2017)

Approval process[edit]

In January 2016, Eli Lilly submitted a new drug application to the US FDA for the approval of baricitinib to treat moderately-to-severely active rheumatoid arthritis.^[1]

In December 2016, the European Committee for Medicinal Products for Human Use (CHMP) recommended the approval of baricitinib as a therapy for RA.^[2] European approval was granted in February 2017.^[3]

Despite widespread expectations that the FDA would approve baricitinib for RA,^[9] in April 2017, the FDA issued a rejection, citing concerns about dosing and safety.^[10][11]

In April 2018, and FDA Advisory Committee recommended approval for baricitinib 2mg for the treatment of rheumatoid arthritis.^[5]

See also[edit]

Other JAK inhibitors include tofacitinib, currently approved for the treatment of RA,^[12] and ruxolitinib.^[13]

References[edit]