Baricitinib

CLASS OF DRUG

• Janus kinase (JAK) inhibitor

PHARMACEUTICS

• 2mg or 4mg film-coated tablets

MECHANISM OF ACTION

• JAK1/2 inhibitors block the Janus-associated receptor tyrosine kinnases JAK1 and JAK2.
  • JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell.
  • JAK1/2 inhibitors block the signalling pathways of multiple cytokines, including IL-2, IL-6, IL-12, and interferons.  
  • As such they are more focussed than corticosteroids (potential for less side-effects) but have a wider spectrum of action than monoclonal antibodies (potential for greater effects).
• Baricitinib also inhibits AP2-associated protein kinase 1 (AAK-1), which regulates endocytosis in alveolar type II cells, but it is uncertain if this action significantly affects SARS-CoV-2 virus replication in vivo.

INDICATIONS

• Moderate-to-severe active rheumatoid arthritis
  • patients who have had an inadequate response to, or are intolerant to, one or more disease-modifying anti-rheumatic drugs as monotherapy or in combination with methotrexate
• Atopic dermatitis (moderate-severe)
• COVID19 disease
  • hospitalised patients who require supplemental oxygen
    • supplemental oxygen includes high-flow oxygen, non-invasive ventilation, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO).

CONTRAINDICATIONS/ PRECAUTIONS

• Absolute lymphocyte count <0.5 x10E9 cells /L 
• absolute neutrophil count <1 x10E9 cells /L
• haemoglobin less than 80 g/L 
• Tuberculosis

Cautions

• Active, chronic or recurrent infection (interrupt treatment if no response to standard therapy)
• risk of diverticulitis
• risk of viral reactivation
• severe hepatic impairment
• renal impairment (GFR <30 mL/min/1.73 m2)

DOSING

PO

• 4mg po daily (adults), or
• 2mg po daily if age >75 years or dose reduction due to: history of infections or sustained control of rheumatoid arthritis disease activity

PHARMACOKINETICS

• A: oral ioavailability 79%; peak plasma levels at 0.5-3h; slightly affected by food (14% less bioavailability)
• D: Protein binding 50%; VD ~1L/kg
• M: minority is hepatically metabolised by CYP3A4 enzymes (<10%)
• E: elimination t1/2 =12.5 hours; 75% exreted in urine and 20% in faeces; clearance ~10L/kg/min

ADVERSE EFFECTS

Common

• Lymphopenia, anemia, and neutropenia
• opportunistic infections/ reactivation (e.g. herpes simplex virus and varicella zoster virus)
• Thrombocytosis
• Dyslipidemia 
• Oropharyngeal pain
• Nausea

Uncommon

• Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Acne
• Neutropenia
• Weight gain
• Diverticulitis

DRUG-DRUG INTERACTIONS (DDIs)

• Potential additive effect with other immunosuppressants.
• Probenecid inhibits renal excretion of baricitinib by ~ 50%
• Use with live, attenuated vaccines during, or immediately prior to, baricitinib therapy is not recommended. 

PREGNANCY/ LACTATION

• Category D (contraindicated in pregnancy)
• Contraception advised during and up to 1 week after treatment with baricitinib
• Enters breast milk in animal studies (avoid if possible)

EVIDENCE

COVID19

• ACTT-2 Trial (Kalil et al, 2020)
  • Small randomised controlled trial that found that barictinib in combination with Remdesivir accelerated time to recovery compared with Remdesivir alone. It was not powered to detect a mortality difference.
• COV-BARRIER trial (Marconi et al, 2021)
  • multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial (n= 1525) of non-mechanically ventilated COVID19 pneumonia pateints with atleast one elevated inflammatory marker (CRP, D-dimer, ferritin, or LDH). There was no difference in the primary outcome, a composite endpoint of progression in NIAID-OS (score 6,7 or 8) by Day 28. However, the secondary outcome of mortality at 60 days was improved for baricitinib: 10% vs 15% (HR 0.62, 95% CI 0.47-0.83, p= 0.005).
  • Data from the COV-BARRIER extension study (Ely et al, 2021 preprint) also suggests baricitinib is safe and effective in patients hospitalised with COVID-19 who require mechanical ventilation or ECMO (n=101; 86% had concomitant corticosteroid therapy; all cause mortality at 28 days for baricitinib versus placebo was 39·2% vs 58·0%; hazard ratio [HR]=0·54 [95%CI 0·31–0·96]; p=0·030).

MONITORING

• Monitor
  • Lipid profile
  • Liver function tests
  • Full blood count (hemoglobin, neutrophils, platelets)
• Baseline testing for hepatitis B, HCV and tuberculosis 

REFERENCES

FOAM and web resources

• Baricitinib | C16H17N7O2S – PubChem
• TGA Product Information – Baricitinib
• The Bottom Line – COV-BARRIER
• PulmCrit – Baricitinib for COVID-19: The rise of the jakinibs

Journal articles

• Assadiasl S, Fatahi Y, Mosharmovahed B, Mohebbi B, Nicknam MH. Baricitinib: From Rheumatoid Arthritis to COVID-19. J Clin Pharmacol. 2021 Oct;61(10):1274-1285. doi: 10.1002/jcph.1874. Epub 2021 Jun 12. PMID: 33870531; PMCID: PMC8250677. [article]
• Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus Standard of Care for Hospitalised Adults with Covid-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomised, Placebo-Controlled Trial. Infectious Diseases (except HIV/AIDS); 2021. [preprint article; not yet peer reviewed]
• Kalil A, Patterson T, Mehta A, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. Published online December 11, 2020. doi:10.1056/NEJMoa2031994 [article]
• Marconi VC, Ramanan AV, de Bono S, et al; COV-BARRIER Study Group. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021 Aug 31:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3. Epub ahead of print. Erratum in: Lancet Respir Med. 2021 Sep 8;: PMID: 34480861; PMCID: PMC8409066. [article]