Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19

Abstract

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.

Keywords: COVID-19; JAK-inhibitor; Janus-associated kinase inhibitor; SARS-CoV-2; baricitinib; severe acute respiratory syndrome.

Figure 1

Janus‐associated kinase/signal transducers and activators of transcription (JAK/STAT) pathway showing baricitinib inhibition of JAK complexes. GM‐CSF = granulocyte‐macrophage colony‐stimulating factor; IFNγ = interferon gamma. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Baricitinib inhibition of viral endocytosis. AAK1 = AP2‐associated protein kinase 1; ACE2 = angiotensin‐converting enzyme 2; GAK = G‐associated kinase; SARS‐CoV‐2 = severe acute respiratory syndrome‐coronavirus 2. [Color figure can be viewed at wileyonlinelibrary.com]