Abrocitinib

The Janus kinase (JAK) family is a group of cytoplasmic tyrosine kinases that mediate signaling pathways activated by various cytokines. By influencing the JAK-STAT signaling pathway, JAK1 is involved in numerous processes of cell proliferation and differentiation. Janus kinases phosphorylate and activate signal transducers and transcriptional activators (STATs), which in turn modulate intracellular activity, including gene expression. Inhibition of JAK1 modulates these signaling pathways by preventing the phosphorylation and activation of STATs.

Abrocitinib is a Janus kinase (JAK) inhibitor approved since December 19, 2021 for the oral treatment of moderate to severe atopic dermatitis in adults. After baricitinib and upadacitinib, abrocitinib is another oral Janus kinase (JAK) inhibitor for this indication.

Absorption: Abrocitinib is absorbed with an oral absorption of over 91%. The absolute oral bioavailability is about 60%. Peak plasma concentrations are reached after 1 hour. Steady-state plasma concentrations are reached within 48 hours after once-daily administration. Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites are equally distributed between erythrocytes and plasma.

Metabolism: In vitro metabolism of abrocitinib is mediated by several CYP enzymes: CYP2C19 (approx. 53%), CYP2C9 (approx. 30%), CYP3A4 (approx. 11%) and CYP2B6 (approx. 6%). Of the 3 circulating metabolites, M1 and M2 have a similar JAK inhibitory profile to abrocitinib, while M4 is pharmacologically inactive.

Elimination: The elimination half-life of abrocitinib is approximately 5 hours. Abrocitinib is eliminated mainly by metabolic clearance mechanisms. Less than 1% of the dose is excreted in the urine as unchanged drug. The metabolites of abrocitinib, M1, M2 and M4, are predominantly excreted renally and are substrates of the OAT3 transporter.

The oral treatment of moderate to severe atopic dermatitis in adults who are candidates for systemic therapy.

Abrocitinib is for oral use and should be taken once daily at approximately the same time of day, regardless of meals. Taking it with a meal may reduce nausea.

Abrocitinib is contraindicated during breastfeeding, as the active substance is excreted in breast milk and a risk to newborns/infants cannot be ruled out.

The recommended starting dose of abrocitinib is 200 mg once daily. A starting dose of 100 mg once daily is recommended for patients aged 65 years and older. During treatment, the dose can be reduced or increased depending on tolerability and efficacy. The lowest effective dose should be considered for maintenance therapy. The maximum daily dose is 200 mg.

The most common side effects reported during treatment with abrocitinib are:

• Nausea (15.1%)
• Headache (7.9%)
• Acne (4.8%)
• Herpes simplex (4.2%)
• Increased creatine phosphokinase in the blood (3.8%)
• Vomiting (3.5%)
• Dizziness and (3.4%)
• Upper abdominal pain (2.2%)

The most common serious side effects are infections (0.3%), which is why patients should be closely monitored for signs and symptoms of infection during and after treatment with abrocitinib.

Serious infections have been reported in patients treated with abrocitinib. The most common serious infections in clinical trials were herpes simplex, herpes zoster and pneumonia. Patients should be tested for tuberculosis before starting treatment with abrocitinib. Viral reactivation is possible with abrocitinib, including cases of reactivation of herpes viruses (e.g. herpes zoster, herpes simplex), which is why screening for viral hepatitis should be carried out before starting and during therapy.

The use of live attenuated vaccines should be avoided during or immediately prior to treatment.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving abrocitinib, therefore abrocitinib should be used with caution in patients at high risk of DVT/ PE. Factors that should be considered when assessing the risk of DVT/LE include older age, obesity, history of DVT/LE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, and patients undergoing major surgery or prolonged immobilization.

Malignancies, including non-melanoma skin cancer (NMSC), have been observed in clinical trials of abrocitinib. However, the clinical data are insufficient to assess a possible association. Long-term safety evaluations are currently underway.

Abrocitinib therapy should not be initiated in patients with a platelet count of < 150 × 103/mm3, an absolute lymphocyte count of < 0.5 × 103/mm3, an absolute neutrophil count of < 1.2 × 103/mm3 or a hemoglobin level of < 10 g/dL.

There are reports of dose-dependent increases in blood lipid levels with abrocitinib, which is why lipid parameters should be checked approximately 4 weeks after the start of therapy and subsequently according to the patient's risk of cardiovascular disease.

Concomitant use of biological immunomodulators, strong immunosuppressants such as ciclosporin, or other Janus kinase (JAK) inhibitors with abrocitinib is not recommended, as the risk of additive immunosuppression cannot be excluded.

The following interactions must be taken into account during therapy with Cibinqo:

Possible influence of other drugs on abrocitinib

Abrocitinib is mainly metabolized via the enzymes CYP2C19 and CYP2C9 and to a lesser extent via the enzymes CYP3A4 and CYP2B6. The active metabolites are excreted via the kidneys and are substrates of the organic anion transporter 3 (OAT3).

Drugs that are inhibitors or inducers of these enzymes and transporters could therefore affect the exposure to abrocitinib and/or its active metabolites.

Concomitant use with CYP2C19/CYP2C9 inhibitors

When abrocitinib was co-administered with fluvoxamine (a strong CYP2C19 and moderate CYP3A inhibitor) or fluconazole (a strong CYP2C19 and moderate CYP2C9 and CYP3A inhibitor), abrocitinib drug exposure increased by 91% and 155%, respectively, compared to administration alone

Concomitant use with CYP2C19/CYP2C9 inducers: administration of 200 mg abrocitinib after several doses of rifampicin, a strong inducer of CYP enzymes, led to a reduction in abrocitinib drug exposure of approximately 56%.

Concomitant use with drugs that increase the pH in the stomach: The absorption of abrocitinib could be reduced due to the reduced solubility of abrocitinib at a pH above 4.

Abrocitinib must not be used during pregnancy or while breastfeeding. In addition, abrocitinib must not be taken in the case of:

• hypersensitivity to the active substance or any of the other ingredients mentioned
• active, serious systemic infections, including tuberculosis
• severe liver dysfunction
• pregnancy
• Abrocitinib is contraindicated during pregnancy, as animal studies have shown reproductive toxicity:

^Cibinqo® (Pfizer)

The approval is based on the results of five clinical studies of the global development program JADE (JAK1 Atopic Dermatitis Efficacy and Safety). The studies investigated the improvement of atopic dermatitis. This was measured using various parameters such as:

• the Investigator Global Assessment (IGA)
• the Eczema Area and Severity Index (EASI) and
• the Peak Pruritus Numerical Rating Scale (PP-NRS)

measured. There was evidence of significant improvements in symptom relief and disease control with abrocitinib compared to placebo.

In a comparison of abrocitinib with the monoclonal IgG4 antibody dupilumab , abrocitinib 200 mg/day was more effective than dupilumab in adults with moderate to severe atopic dermatitis under topical background therapy. The improvements were mainly related to the early reduction of itching. Both treatments were well tolerated over 26 weeks (Bieber T et al. 2021) (i.e. Janus kinase inhibitors and atopic dermatitis.

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2. Bieber T et al. (2021) Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med 384: 1101-1112.
3. Gadina M et al. (2019) Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology. 58(Suppl 1): i4-i16.
4. Honstein T et al. (2020) The show must go on: an update on clinical experiences and clinical studies on novel pharmaceutical developments for the treatment of atopic dermatitis. Curr Opin Allergy Clin Immunol 20: 386-394.
5. Reich K et al. (2022) Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized, double-blind, multicentre phase 3 trial. Lancet 400:273-282.
6. Wan H et al. (2022) Comparative efficacy and safety of abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis: A network meta-analysis. Dermatol Ther 35:e15636.