Baricitinib

Uses

Baricitinib is a selective and reversible inhibitor of Janus kinase JAK1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50 values of 5.9, 5.7, 53 and > 400 nM, respectively. Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.

Baricitinib is also used to associated treatment for these conditions: Coronavirus Disease 2019 (COVID‑19), Moderate, active Rheumatoid arthritis, Severe, active Rheumatoid arthritis

How Baricitinib works

JAK enzymes are part of the family of tyrosine kinases that constitutively bind to the intracellular domains of cytokine receptors and promote the signalling cascades of cytokines and growth factors involved in haematopoiesis, inflammation and immune function that are also implicated in the pathogenesis of rheumatoid arthritis . Circulating proinflammatory cytokines bind to these cell surface receptors. Upon binding of extracellular cytokines and growth factors, JAKs are phosphorylated and activate signal transducers and activators of transcription (STATs). Through the signalling cascades, inflammatory cytokine and chemokine transcription is induced to form inflammatory mediators including IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ and GM-CSF .

Baricitinib selectively and reversibly inhibits JAK1 and JAK2 to modulates their signalling pathways, thereby reducing the phosphorylation and activation of STATs . In isolated enzyme assays, baricitinib also exhibited an inhibitory effect on other types of JAK enzymes,Tyrosine Kinase 2 and JAK3, at higher concentrations needed for JAK1/2 inhibition.

Dosage

Baricitinib dosage

The recommended dose of Baricitinib is 2 mg once daily. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs.Anemia: Avoid initiation or interrupt Baricitinib in patients with hemoglobin less than 8 g/dL.Lymphopenia: Avoid initiation or interrupt Baricitinib in patients with an Absolute Lymphocyte Count less than 500 cells/mm3.Neutropenia: Avoid initiation or interrupt Baricitinib in patients with an Absolute Neutrophil Count less than 1000 cells/mm3.Moderate Renal Impairment: Reduce dose to 1 mg once daily

Side Effects

Adverse reactions (greater than or equal to 1%) include: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster.

Toxicity

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Although unknown clinical relevance, bariticinib has shown to decrease the counts in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissues of the immune system in mice, rats and dogs. Opportunistic infections related to demodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure. At doses approximately 6-36 times the indicated doses in humans, decreases in red blood cells was observed in mice, rats and dogs.

In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively). Baricitinib decreased fertility and conception indices in a combined male/female rat fertility study. Decreased overall maing performance was likely due to altered reproductive functions of female rats, as there were no detectable changes on spermatogenesis or semen/sperm endpoints in male rats. In female rats, there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos. In a dog pre- and postnatal development study, there were decreased pup weights at exposure 4 times the human exposure and decreased postnatal survival following exposure 21 times the human exposure. Baricitinib was detected in the milk of lactating rats {FDA Label].

Clinical relevance in humans is not yet established. All the adverse reactions associated with baricitinib are expected to occur dose-dependently.

Precaution

• Serious Infections: Avoid use of Baricitinib in patients with active, serious infection, including localized infections. If a seriousinfection develops, interrupt Baricitinib therapy until the infection is controlled. Do not give BARICITINIB to patients with activetuberculosis.• Thrombosis: Use with caution in patients who may be at increased risk.• Gastrointestinal Perforations: Use with caution in patients who may be at increased risk.• Laboratory Assessment: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes,and lipids.• Vaccinations: Avoid use of Baricitinib with live vaccines.

Food Interaction

• Take at the same time every day.
• Take with or without food.

Baricitinib Cholesterol interaction

[Moderate] In controlled clinical trials in patients with rheumatoid arthritis, baricitinib treatment was associated with dose-related increases in lipid parameters including total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.

Lipid parameters should be assessed at baseline and about 12 weeks after initiation of therapy in patients with rheumatoid arthritis.

Patients should be managed according to clinical guidelines for the management of hyperlipidemia.

Baricitinib Drug Interaction

Unknown: amoxicillin / clavulanate, azithromycin, methohexital, celecoxib, colchicine, diltiazem, immune globulin intramuscular, arginine, levocarnitine, cysteine, lithium, metoprolol, valproic acid, thiamine, cyanocobalamin, pyridoxine, ascorbic acid, cholecalciferol, phytonadione, menaquinone

Baricitinib Disease Interaction

Major: infections, tuberculosis, cardiovascular risk, malignancy, thrombosisModerate: diabetes, GI perforation, hepatic impairment, hyperlipemia, laboratory abnormalities, renal dysfunction, vaccination, viral hepatitis

Volume of Distribution

Mean volume of distribution following intravenous infusion administration is 76 L .

Elimination Route

Baricitinib diaplays a dose-proportional increase in systemic exposure in the therapeutic dose range with linear pharmacokinetics. When orally administered, baricitinb is rapidly absorbed with an oral bioavailability of approximately 79 % (CV = 3.94 %). It has a median time to reach peak plasma concentration (Tmax) of 1hour (range: 0.5-3hours). Food consumption affects the exposure by decreasing it by up to 14 %, and decreasing the peak plasma concentration (Cmax) by up to 18 % and Tmax by 0.5 hours .

Half Life

Mean half-life in patients with rheumatoid arthritis is approximately 12.5 hrs (CV = 27.4 %) .

Clearance

Mean apparent clearance (CL/F) in patients with rheumatoid arthritis is approximately 9.42 L/hr (CV = 34.3 %) .

Elimination Route

In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and feces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in feces) constituting approximately 5 % and 1 % of the dose, respectively .

Pregnancy & Breastfeeding use

Pregnancy & Lactation: There are no adequate and well-controlled studies in pregnant women. It is not known whether Baricitinib is excreted in human milk.Pediatric Use: The safety and effectiveness of Baricitinib in pediatric patients have not been established.Geriatric Use: No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Hepatic Impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of Baricitinib has not been studied in patients with severe hepatic impairment and is therefore not recommended.Renal Impairment: Renal function was found to significantly affect Baricitinib exposure. The recommended dose of Baricitinib in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 60 mL/min/1.73 m2) is 1 mg once daily. Baricitinib is not recommended for use in patients with severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2)

Interaction with other Medicine

The recommended dose of Baricitinib in patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors (e.g., probenecid) is 1 mg once daily.

Innovators Monograph

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