ritlecitinib

Action and Spectrum

Actions and Spectrum: 

ritlecitinib is an oral Janus Kinase (JAK) inhibitor with JAK3-selective properties. It works by inhibiting the activity of Janus Kinase enzymes, particularly JAK3. By inhibiting JAK3, ritlecitinib interferes with the signaling pathways involved in inflammation and immune responses. This mechanism of action makes it a potential therapeutic option for various conditions characterized by dysregulated immune responses. 

Spectrum:  

• Alopecia Areata: ritlecitinib is being investigated as a potential treatment for moderate-severe alopecia areata (AA), an autoimmune form of hair loss. AA can range from localized hair loss to complete body hair loss. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Headache (10.8%) 

1-10% 

Stomatitis (1.5%) 

Rash (5.4%) 

Acne (6.2%) 

Herpes zoster (1.5%) 

Increased CPK (1.5%) 

Dizziness (2.3%) 

Diarrhea (10%) 

Urticaria (4.6%) 

Decreased RBCs (1.5%) 

Folliculitis (3.1%) 

Atopic dermatitis (2.3%) 

Pyrexia (3.1%) 

Black Box Warning

Black Box Warning: 

• Serious infections: The elevated likelihood of severe bacterial, viral, fungal, and opportunistic infections, which may result in hospitalization or fatality, encompasses tuberculosis (TB) as well. 
• Enhanced mortality: In patients with rheumatoid arthritis (RA), the use of another Janus kinase inhibitor (JAK) is associated with a greater risk of overall mortality, including sudden cardiovascular (CV) death, when compared to TNF blockers. 
• Thrombosis: Instances of thrombosis have been reported. 
• Malignancies: Occurrences of malignancies have been observed. 
• MACE: There is an increased incidence of major adverse cardiovascular events (MACE). 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: Individuals with known hypersensitivity or allergic reaction to ritlecitinib or any of its components should not use the medication. 
• Active Infections: ritlecitinib may suppress the immune system, which can increase the risk of infections. Therefore, it may be contraindicated in individuals with severe active infections or systemic fungal, bacterial, or viral infections. 
• Pregnancy and Breastfeeding: JAK inhibitors have the potential to harm the fetus or breastfeeding infant based on animal studies. Therefore, ritlecitinib may be contraindicated in pregnant women or breastfeeding women. 
• Severe Liver Dysfunction: ritlecitinib may impact liver function and cause liver enzyme elevations. In cases of severe liver dysfunction or impairment, ritlecitinib may be contraindicated. 

Caution 

• Infections: JAK inhibitors can suppress the immune system, which may increase the risk of infections. Patients taking ritlecitinib should be monitored for signs of infections, and caution should be exercised in patients with a history of chronic/recurrent infections. Serious or opportunistic infections should be promptly evaluated and treated. 
• Malignancies: JAK inhibitors have been associated with an increased risk of malignancies, including lymphoma and non-melanoma skin cancer. Regular monitoring for signs of malignancies and appropriate screening measures should be implemented. 
• Thrombosis: JAK inhibitors have been associated with an enhanced risk of thromboembolic events, including deep vein thrombosis and pulmonary embolism. Patients with a history of thrombosis or risk factors for thrombosis should be carefully evaluated before initiating ritlecitinib therapy. 
• Hepatotoxicity: JAK inhibitors can cause liver enzyme elevations. Liver function should be monitored periodically, and caution should be exercised in patients with pre-existing liver disease or elevated liver enzymes. 
• Lipid Abnormalities: JAK inhibitors have been associated with changes in lipid profiles, including increases in cholesterol and triglyceride levels. Lipid monitoring and management according to clinical guidelines are recommended during ritlecitinib treatment. 
• GI Perforation: There have been reports of gastrointestinal perforation in patients receiving JAK inhibitors. Patients with a history of diverticulitis, Crohn’s disease, or other conditions predisposing to gastrointestinal perforation should be closely monitored. 
• Interactions and Contraindications: ritlecitinib may interact with other medications or have contraindications in specific patient populations. Reviewing the complete list of medications, including over-the-counter drugs and supplements, and discussing potential interactions or contraindications with healthcare professionals is essential. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

ritlecitinib is a novel pharmacological agent in the Janus kinase (JAK) inhibitor class. It exerts its pharmacological effects by selectively targeting and inhibiting JAK enzymes, specifically JAK1 and JAK3. By doing so, ritlecitinib interferes with the JAK-STAT signaling pathway, which plays a important role in immune response and inflammatory processes.

This inhibition leads to a reduction in the production and release of pro-inflammatory cytokines, like interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Consequently, ritlecitinib exhibits potent anti-inflammatory and immunomodulatory properties. The pharmacological profile of ritlecitinib suggests its potential therapeutic use in various immune-mediated disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. 

Pharmacodynamics: 

Mechanism of action: The action of ritlecitinib involves selective inhibition of Janus kinase (JAK) enzymes, particularly JAK1 and JAK3. JAKs are intracellular enzymes that play a crucial role in the signaling pathways of various cytokines and growth factors involved in immune and inflammatory responses. 

By binding to the ATP-binding site of JAK1 and JAK3, ritlecitinib prevents their activation and subsequent phosphorylation. This inhibition interferes with the JAK-STAT (signal transducer and activator of transcription) signaling pathway, which transmits signals from cytokine receptors to the nucleus. 

The JAK-STAT pathway is responsible for the production and release of several pro-inflammatory cytokines, such as interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). By inhibiting JAK1 and JAK3, ritlecitinib reduces the signaling cascade triggered by these cytokines, thereby suppressing the production of pro-inflammatory mediators. 

The inhibition of JAK1 and JAK3 by ritlecitinib leads to the downregulation of inflammatory pathways and modulation of immune responses. This results in ameliorating symptoms and reducing inflammation in immune-mediated disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. 

Pharmacokinetics: 

Absorption 

ritlecitinib is administered orally and is rapidly absorbed from the gastrointestinal tract. The bioavailability of ritlecitinib is high, indicating that a significant portion of the administered dose reaches systemic circulation. 

Distribution 

Once absorbed, ritlecitinib distributes throughout the body. It has a moderate volume of distribution, suggesting that it is also distributed into extravascular compartments. The drug is known to bind extensively to plasma proteins, primarily albumin. 

Metabolism 

ritlecitinib undergoes extensive hepatic metabolism primarily via cytochrome P450 (CYP) enzymes, particularly CYP3A4. The metabolites formed are pharmacologically inactive. The main metabolic pathway involves oxidative metabolism, leading to the formation of multiple metabolites. Some of these metabolites may possess weak inhibitory activity against other CYP enzymes. 

Elimination and Excretion 

Following metabolism, ritlecitinib, and its metabolites are eliminated primarily through renal and biliary excretion. Nearly half of the administered dose is excreted in the urine, while the remaining portion is excreted in the feces. The drug has a relatively long elimination half-life, allowing for once-daily dosing. 

Adminstartion

Administration: 

Oral administration 

ritlecitinib is typically administered orally in the form of tablets or capsules. The specific dosing instructions for ritlecitinib may vary depending on the condition being treated, individual patient factors, and the prescribing healthcare professional’s guidance. Following the prescribed dosage and administration instructions the healthcare provider provides is essential. 

Generally, ritlecitinib is taken once daily, with or without food. The tablet or capsule should be swallowed whole with a glass of water and should not be crushed, chewed, or split unless otherwise instructed by the healthcare professional. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ritlecitinib 

Why do we use ritlecitinib? 

ritlecitinib may have potential therapeutic applications in various immune-mediated disorders and inflammatory conditions.  

• Rheumatoid Arthritis: ritlecitinib may be beneficial in treating rheumatoid arthritis, pain, and stiffness. 
• Psoriasis: It is a chronic skin condition caused by an overactive immune system. JAK inhibitors, including ritlecitinib, have shown promise in treating psoriasis by reducing inflammation and improving skin symptoms. 
• Inflammatory Bowel Disease (IBD): ritlecitinib could help manage inflammatory bowel diseases like Crohn’s disease and ulcerative colitis, which involve chronic inflammation of the gastrointestinal tract. 
• Other Immune-Mediated Disorders: JAK inhibitors have been investigated for their potential in other immune-mediated conditions such as systemic lupus erythematosus (SLE), atopic dermatitis, and alopecia areata.