Tofacitinib vs Baricitinib

## Overview

Tofacitinib (Xeljanz) was the first Janus kinase (JAK) inhibitor approved for RA. Baricitinib (Olumiant) is a selective JAK1/JAK2 inhibitor with once-daily dosing, unique approval for alopecia areata, and pivotal data in COVID-19 hospitalized patients. Both carry class-wide FDA boxed warnings for serious infections, malignancy, MACE, and thrombosis.

## Mechanism of Action

Tofacitinib: primarily inhibits JAK1 and JAK3, with less JAK2 inhibition. This reduces signaling of cytokines that use the gamma-c chain (IL-2, IL-4, IL-7, IL-15, IL-21) and IL-6, Type I/II interferons. Baricitinib: selectively inhibits JAK1 and JAK2, reducing signaling of cytokines using JAK1/JAK2 (IL-6, GM-CSF, interferons, EPO, TPO).

## Pharmacokinetics

Tofacitinib: BID (5 or 10 mg) or extended-release once daily (11 mg XR), half-life ~3 h (IR), renal + hepatic elimination. Baricitinib: once daily (2 mg or 4 mg), half-life ~12 h, ~75% renal excretion unchanged.

## Clinical Efficacy and Safety

Both effective for RA. Tofacitinib ORAL Surveillance trial (post-marketing mandated study): increased MACE and malignancy vs. TNF inhibitors, leading to black box warning and restricted indication. Baricitinib has a similar boxed warning. Baricitinib 4 mg studied in COV-BARRIER trial (hospitalized COVID-19): significant mortality reduction.

## Renal Impairment

Baricitinib (75% renal excretion) requires dose reduction in CKD. Tofacitinib has mixed renal/hepatic clearance with less renal dependence.

## Key Takeaways

- Both JAK inhibitors with class-wide boxed warnings for thrombosis, infection, malignancy, MACE
- Baricitinib: once daily, JAK1/2 selective, unique alopecia areata and COVID-19 approvals
- Tofacitinib: first-in-class JAK inhibitor; also approved for PsA, UC, JIA