APREZO

Indications

• Active psoriatic arthritis
• Moderate to severe chronic plaque psoriasis
• Behcet's disease-related oral ulcers

Dosage

Adults: Initially 10 mg daily on day 1, then 10 mg twice daily on day 2, then 10 mg in the morning and 20 mg in the evening on day 3, then 20 mg twice daily on day 4, then 20 mg in the morning and 30 mg in the evening on day

Mechanism of action

Apremilast inhibits phosphodiesterase type-4 (PDE4), which results in increased levels of cyclic adenosine monophosphate (cAMP) within cells. Elevated cAMP levels lead to the suppression of pro-inflammatory mediators such as TNF-α, IL-17, and IL-23. This cascade ultimately reduces inflammation and alleviates symptoms associated with conditions like psoriatic arthritis and Behcet's disease.

Pharmacodynamics

Apremilast reduces the levels of various inflammatory cytokines, including IL-1α, IL-6, IL-8, IL-10, MCP-1, MIP-1β, MMP-3, and TNF-α. This action helps relieve symptoms of psoriasis and Behcet's disease, including oral ulcers and skin lesions. However, apremilast can also lead to weight loss and exacerbate depression, necessitating careful monitoring for mood changes and weight management during treatment.

Pharmacokinetics

Apremilast is administered orally and has a bioavailability that is not fully established. It is primarily metabolized by the liver, with its pharmacokinetics affected by concomitant medications. The drug is known to have a half-life that supports twice-daily dosing after an initial titration period. Patients should be monitored for therapeutic efficacy and adverse effects throughout treatment.

Contra-indications

• History of suicidal thoughts or behavior
• Severe renal impairment
• Hypersensitivity to apremilast or any excipients

Adverse effects

• Nausea
• Diarrhea
• Headaches
• Weight loss
• Insomnia
• Increased risk of infections
• Suicidal thoughts and behaviors
• Gastrointestinal hemorrhage
• Rash

Interactions

• St. John's Wort (severe interaction, decreases exposure)
• Mitotane (unknown interaction, may decrease exposure)

Precautions

• Monitor for signs of depression or suicidal thoughts, especially in patients with a history of psychiatric illness
• Assess weight regularly; consider discontinuation if significant weight loss occurs
• Caution in patients with a history of psychiatric disorders

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on use in pregnant women.

Breast-feeding

Unknown if excreted in human milk; caution is advised.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablet: 10 mg, 20 mg, 30 mg

Mechanism of action

The full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms. Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin. Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis. Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-a (TNF-a), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-a, and interleukin (IL)-2

Pharmacodynamics

Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast.