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, high-flow oxygen and/or non-invasive ventilation.

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 breat 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).

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

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]
  • 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]

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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