Janus Kinase (JAK) Inhibitors: Tofacitinib, Ruxolitinib, Baricitinib and Abrocitinib

Mechanism

Pharmacological Class and Group

Synthetic small molecules aimed at the selective inhibition of the non-receptor tyrosine kinase family Janus Kinases (JAK1, JAK2, JAK3, TYK2). Ruxolitinib and Tofacitinib are topical and systemic; Baricitinib and Abrocitinib are oral.

Mechanism of Action

The extracellular binding of multiple cutaneous proinflammatory and immunoregulatory cytokines (such as IL-2, IL-4, IL-6, IL-15, IL-21, IL-31, and type I and II interferons) to their specific receptors induces homodimerization or heterodimerization of intracellularly coupled Janus Kinases in the membrane.

JAK-STAT Transduction Pathway Inhibition Mechanism

1. Reversible Inhibition of Phosphorylation: JAK inhibitors passively penetrate the cell interior and competitively bind to the ATP-binding catalytic domain of Janus kinases (reversibly blocking their enzymatic kinase capacity).

2. Blockade of STAT Coupling: As JAK kinases are inhibited, autophosphorylation and subsequent phosphorylation of signal transducers and activators of transcription (STAT, from STAT1 to STAT6) are prevented.

3. Lack of Homodimerization and Translocation: Without phosphorylation, STAT proteins cannot form stable homodimers or heterodimers and their nuclear translocation is interrupted:

JAK inhibitor JAK1/2 phosphorylation Non-dimerization of STAT Genetic Silencing of Cytokines

4. Rapid Suppression of Pruritus and Inflammation: The gene synthesis of multiple inflammatory factors and chemokines is simultaneously blocked. It should be noted that the blockade of IL-31 (the itch-inducing cytokine that acts through the JAK1/JAK2 pathway) results in a clinical effect of immediate relief of itch in less than 24 hours.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Excellent oral absorption, bioavailability greater than 80% for abrocitinib and baricitinib. The intake of fatty foods does not alter its overall AUC significantly.
• Metabolism:
  • Baricitinib: It is minimally metabolized in the liver (less than 10% by CYP3A4). It has low potential for direct hepatic metabolic interactions.
  • Abrocitinib and Tofacitinib: Extensive hepatic phase I metabolism predominantly mediated by the cytochrome isoenzymes CYP3A4 and CYP2C19. They produce inactive polar metabolites.
• Excretion: Baricitinib is mainly excreted unchanged in urine through renal glomerular filtration and OAT3-mediated active tubular secretion (75%). Abrocitinib and tofacitinib are eliminated in a mixed manner (hepatic/renal).
• Half-life (t_1/2): Short elimination half-lives of 3 to 12 hours, requiring daily administration and allowing immediate systemic clearance in case of toxicity.

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Atopic Dermatitis (Abrocitinib, Baricitinib orally; Ruxolitinib topical): Excellent skin clearance rates and control of refractory chronic itch.
• Severe Alopecia Areata and universal course (Baricitinib): First drug approved systemically that manages to restimulate follicular growth by deactivating the immunological attack of CD8+/NKG2D+ cytotoxic T lymphocytes.
• Nonsegmental Vitiligo (Ruxolitinib Cream): Approved topically for epidermal repigmentation.
• Plaque Psoriasis / Arthritic Psoriasis (Systemic Tofacitinib): Immune control of plaque and joint pain.

Dosage and Clinical Adjustment

Baricitinib (Alopecia Areata Severe):

• Standard Dose: 4 mg orally once a day, with or without food.
• Maintenance: Once satisfactory sustained follicular growth is achieved, reduce the dose to 2 mg per day if clinical plaque control permits.

Abrocitinib (Atopic Dermatitis):

• Starting Dose: 100 mg or 200 mg orally once a day. The 200 mg/day dose offers the highest rate of immediate clearance and rapid itch control.

Adjustment in Kidney Failure:

• Baricitinib: Reduce the dose by 50% (administer 2 mg per day) if the eGFR is between 30 and 60 mL/min/1.73 m². Absolutely contraindicated if the eGFR is < 30 mL/min/1.73 m².
• Abrocitinib: Reduce the dose by 50% (maximum 100 mg per day) in moderate renal failure (eGFR 30-59 mL/min). Contraindicated if eGFR is < 30 mL/min.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active ingredient.
• Clinically serious active bacterial, fungal or viral infections.
• Latent Tuberculosis Infection not treated with prior chemoprophylaxis.
• Severe kidney or liver failure (Child-Pugh C).
• Pregnancy and Breastfeeding in progress.
• Severe baseline counts: Neutrophils < 1000/mm³, Lymphocytes < 500/mm³, Hemoglobin < 8 g/dL.

Relative Contraindications

• Pre-existing venous thromboembolism (VTE, DVT or pulmonary embolism) risk factors.
• Patients over 65 years of age with prolonged active smoking (increased risk of major cardiovascular events [MACE] and acute myocardial infarction).

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Mild self-limited headache, benign nasopharyngitis, early-onset transient nausea (Abrocitinib).
• Frequent (1%-10%): Upper respiratory infections, moderate elevation of transaminases, elevation of creatine kinase (CK) with an asymptomatic course, mild hypercholesterolemia (elevation of LDL and HDL in parallel), Reactivation of Varicella Zoster (Herpes Zoster) virus.
• Uncommon (0.1%-1%): Neutropenia or mild transient thrombocytopenia, events of Venous Thromboembolism (VTE), malignancy (Lymphoma or non-melanoma skin cancer).

FDA Black Box Warning for JAK Inhibitors

Based on a large long-term safety study of tofacitinib in rheumatoid arthritis (ORAL Surveillance) conducted in patients over 50 years of age with cardiovascular risk factors, a class safety alert applicable to systemic JAK inhibitors was issued:

• Risk of Major Cardiovascular Events (MACE): Modest but statistically significant increase in the rate of nonfatal acute myocardial infarction and ischemic stroke.
• Risk of Venous Thromboembolism (VTE): Formation of deep vein thrombosis and massive pulmonary embolism, possibly linked to secondary blockade of erythropoietin signaling that subtly alters blood rheology.
• Serious Infections: Rapid reactivation of herpes zoster (due to inhibition of local immune clearance of lymphocytes mediated by type I interferons and the IL-15 axis).

It is suggested to avoid the systemic use of JAK inhibitors in patients with a history of recent myocardial infarction, heavy smokers, carriers of active procoagulant mutations (Factor V Leyden) or with a personal history of DVT.

Drug Interactions of Clinical Relevance

• Strong inhibitors of CYP3A4 and CYP2C19 (Fluconazole, Ketoconazole, Fluvoxamine): They double the area under the curve (AUC) of abrocitinib and tofacitinib. Require dose reduction by half or avoidance.
• CYP inducers (Rifampicin): They notably decrease the therapeutic levels of the active drug, nullifying its clinical efficacy.
• OAT3 inhibitors (Probenecid): They significantly increase systemic levels of baricitinib.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Contraindicated. Toxicity studies in preclinical models unequivocally reported skeletal malformations and fetal bone hypoplasia due to interference with trophic growth factor signaling.
• Breastfeeding: Absolutely contraindicated. They are excreted in relevant quantities and pose an unacceptable risk of systemic immunosuppression and delayed development of the infant.