Baricitinib

by Douglas Black, Pharm.D. last updated 2022-01-07 15:22:10.660556-05:00 © Antimicrobial Therapy, Inc.

Baricitinib

Tradename

Usage and Dosing

Baricitinib (Oliumiant)(Lilly) is a Janus Kinase inhibitor (JAK), specifically a JAK-1 and JAK-2 inhibitor.
EUA issued by US FDA on 19 Nov 2020 based on ACTT-2 trial that showed modest improvement when administered in combination with remdesivir in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
- The primary endpoint was time to recovery during the first 28 days: The median time to recovery was shorter in the baricitinib plus remdesivir group (7 days) than in the placebo plus remdesivir group (8 days) in the overall cohort (rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03).
- Recovery time was improved by 8 days in the subset of patients receiving non-invasive ventilation of high-flow oxygen devices at baseline (10 days versus 18 days).
- Rate of progression to death or invasive ventilation was lower in the combination therapy group (12.2% vs. 17.2%; rate ratio, 0.69; 95% CI, 0.50 to 0.95).
- Trend toward lower 28-day mortality in the combination therapy group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09), which did not achieve statistical significance.
- Patients were excluded from the trial if they were receiving corticosteroids: Risks and benefits of baricirinib vis-a-vis dexamethasone, the latter having been shown in the RECOVERY trial to improve survival, are unknown and will require further study. Accordingly, remdesivir plus dexamethasone is preferred over bariticinib + remdesivir, which should be used only in situations where corticosteroids cannot be used.
Randomized, placebo-controlled trial in Brazil (Lancet Respir Med 2021;S2213-2600(21)00331-3) of 1525 patients hospitalized with COVID-19 who had ≥1 elevated inflammatory marker found no difference of Baricitinib compared to placebo for the composite primary endpoint (proportion progressing to high-flow oxygen, noninvasive or invasive mechanical ventilation, or death) 28% (baricitinib) vs. 30% (placebo) but 28-day all-cause mortality was 8% (n=62) for Baricitinib and 13% (n=100) for placebo, a 38% relative reduction in mortality (p=0·0018).
- 78% of patients were receiving systemic corticosteroids while only 19% were receiving remdesivir.
- Baricitinib was most beneficial in those on high-flow oxygen or noninvasive ventilation at baseline.
On 28 July 2021, the EUA was revised to authorize baricitinib alone (without remdesivir) for the treatment of COVID-19 in hospitalized adults and pediatric patients two years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO. Fact sheet here.
Baricitinib exposure is increased when co-administered with strong OAT3 inhibitors, such as probenecid. See dosing recommendations in Major Drug Interactions below.
BLACK BOX warning: serious infections (TB, fungal infections, other opportunistic infections), lymphoma and other malignancies, thrombosis including deep vein thrombosis and pulmonary embolism.

Adult Dose

COVID-19 dose (EUA): 4 mg once daily, with or without food.
Duration of treatment: 14 days or until hospital discharge, whichever comes first.

Pediatric Dose

COVID-19 dose (EUA):
- Age ≥9 years: 4 mg once daily, with or without food.
- Age 2 to <9 years: 2 mg once daily, with or without food.
- Age <2 years: not authorized.
Duration of treatment: 14 days or until hospital discharge, whichever comes first.

Renal Adjustment

Dosing adjustments are based on eGFR.

eGFR (mL/min/1.73 m²)	Age ≥9 years	Age 2 to <9 years
≥60	4 mg q24h	2 mg q24h
30 to <60	2 mg q24h	1 mg q24h
15 to <30	1 mg q24h	Not recommended
<15	Not recommended	Not recommended

Hepatic Adjustment

No dosage adjustment necessary in mild or moderate hepatic impairment.
Not recommended in severe hepatic impairment (no data).

Adverse Effects

Serious infections (TB, fungal infections, other opportunistic infections).
Lymphoma, other malignancies.
Thrombosis, including deep vein thrombosis and pulmonary embolism.
Gastrointestinal perforations.
Hypersensitivity reactions (angioedema, urticaria, rash).
AST, ALT elevations.
Neutropenia, lymphopenia, anemia.
Lipid elevations (total cholesterol, LDL, HDL).

Pharmacology

Pregnancy Category	Insufficient data in humans, toxic in animals
Class	JAK inhibitor
PK/PD Index	No data
Pharmaceutical Preparation	1 mg, 2 mg tablets
COVID-19 Adult Dose	4 mg q24h
Food Effect¹	Take with or without food
Oral Absorption² (%)	80
Tmax (hr)	1
Peak Serum Level³ (μg/mL)	No data
Protein Binding (%)	50
Average Serum Half-life⁴ (hr)	12
Elimination	Primarily renal
Biliary Penetration⁵ (%)	No data
CSF/Blood Penetration⁶ (%)	No data
Therapeutic Levels in CSF⁷	No data
Volume of Distribution⁸ (Vd)	76 L
AUC⁹ (μg*hr/mL)	No data
CYP450, Transporter Interactions	Substrate for OAT3, PGP, BCRP, MATE2-K

Notes:

¹ Adult preparations unless otherwise noted.
² Absorption under optimal conditions.
³ Total drug; adjust for protein binding to determine free drug concentration.

SD = after single dose
SS = steady state after multiple doses

⁴ Assumes CrCl > 80 mL/min
⁵ Peak concentration in bile/peak concentration in serum x 100
⁶ CSF levels with inflammation
⁷ Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
⁸ Volume of Distribution (Vd):

V/F = Vd/oral bioavailability
Vss = Vd at steady state
Vss/F = Vd at steady state/oral bioavailability

⁹ Area under the plasma concentration versus time curve

Major Drug Interactions

Drug	Effect on concentration	Suggested management
Strong OAT3 inhibitors	↑ baricitinib	If dose is 2-4 mg q24h, ↓dose by 50%. If dose is 1 mg q24h, consider stopping OAT3 inhibitor.

Comments

Baricitinib is considered an alternative treatment for hospitalized patients who are hyperemic with severe COVID disease; its use in combination with dexamethasone has not been studied