Baricitinib

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Baricitinib
Baricitinib structure.svg
Clinical data
Trade names Olumiant
Synonyms INCB28050, LY3009104
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 79%
Protein binding 50%
Metabolism CYP3A4 (<10%)
Biological half-life 12.5 hours
Excretion 75% urine, 20% faeces
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
ECHA InfoCard 100.219.080
Chemical and physical data
Formula C16H17N7O2S
Molar mass 371.42 g/mol
3D model (JSmol)

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]

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. Janus kinase 3 is affected much less (IC50 = 53 nM), and tyrosine kinase 2, which belongs to the same enzyme family, even 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 31 clinical trials had been registered for baricitinib of which 24 had completed,[5] and 4 of 6 phase 3 trials had completed.[6]

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,[7] in April 2017, the FDA issued a rejection, citing concerns about dosing and safety.[8][9]

See also[edit]

Other JAK inhibitors include tofacitinib, currently approved for the treatment of RA,[10] and ruxolitinib.[11]

References[edit]

  1. ^ a b "Lilly and Incyte Announce Submission of NDA to FDA for Oral Once-Daily Baricitinib for Treatment of Moderate-to-Severe Rheumatoid Arthritis". Drugs.com. 19 January 2016. 
  2. ^ a b "Summary of opinion for Olumiant" (PDF). European Medicines Agency. 15 December 2016. 
  3. ^ a b "Olumiant: Authorisation details". European Medicines Agency. 16 March 2017. 
  4. ^ a b c d e f g h "Olumiant: EPAR – Product Information" (PDF). European Medicines Agency. 13 February 2017. 
  5. ^ baricitinib trials
  6. ^ baricitinib phase 3 trials
  7. ^ Carroll, J (13 April 2017). "We don’t know when (exactly) Lilly will announce the FDA’s baricitinib decision, but watch out for the looming pricing squabble". Endpoints News. 
  8. ^ Ramsey, L (17 April 2017). "The FDA shot down a new rheumatoid arthritis drug — and the companies that make the drug are tumbling". Business Insider. 
  9. ^ Grant, Ch (14 April 2017). "Surprise FDA Rejection Will Sting This Biotech". The Wall Street Journal. 
  10. ^ "FDA approves Xeljanz for rheumatoid arthritis". 6 November 2012. 
  11. ^ Mesa RA (2010). "Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis". IDrugs. 13 (6): 394–403. PMID 20506062.