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General Description:

Trifarotene, identified by CAS number 895542-09-3, is a notable compound with significant therapeutic applications. Trifarotene is a topical retinoid cream used in the treatment of acne vulgaris that was first approved for use in the United States in October 2019. Retinoids are a class of medications structurally and functionally analogous to , though later generation retinoids such as trifarotene and bear little structural resemblance to vitamin A and are analogous only in function. Trifarotene is considered the first of the "fourth-generation" retinoids due to its uniquely selective activity - this selectivity appears to confer improved efficacy and reduced side effects as compared to older, less selective retinoids.

Indications:

This drug is primarily indicated for: Trifarotene is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Trifarotene undergoes metabolic processing primarily in: Trifarotene is rapidly metabolized in human hepatocytes - its observed half-life in human keratinocytes is >24 hours, whereas half-life in human liver microsomes is approximately 5 minutes. Metabolism of trifarotene is catalyzed primarily by CYP2C9, CYP3A4, CYP2C8, and, to a lesser extent, CYP2B6. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Trifarotene are crucial for its therapeutic efficacy: Systemic absorption of trifarotene is minimal. In a pharmacokinetic study involving 19 subjects, systemic concentrations were only quantifiable in 7 - steady state C_max values ranged from undetectable (<5 pg/mL) to 10 pg/mL and AUC_0-24h ranged from 75 to 104 pg.h/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Trifarotene is an important consideration for its dosing schedule: The terminal half-life of trifarotene is typically between 2 to 9 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Trifarotene exhibits a strong affinity for binding with plasma proteins: Trifarotene is 99.9% protein bound in plasma. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Trifarotene from the body primarily occurs through: Trifarotene is eliminated primarily in the feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Pharmacodynamics:

Trifarotene exerts its therapeutic effects through: Trifarotene exerts its effects via agonism at retinoid receptors - these receptors function to alter DNA transcription, resulting in downstream modulation of the expression of various genes involved in acne pathogenesis. It may be associated with skin irritation and should not be applied to cuts, abrasions, or otherwise damaged skin. As trifarotene may result in photosensitivity, patients should be cautioned to avoid excess sun exposure and to use sunscreen and/or protective clothing if exposure is unavoidable. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Trifarotene functions by: Trifarotene is a potent and selective agonist of retinoic acid receptor-γ (RAR-γ). It has significantly less activity at RAR-β and RAR-α (16- and 65-fold lower than activity at RAR-γ, respectively), and has no activity at retinoid X receptors (RXRs). Agonism at retinoic acid receptors results in dimerization, and the resulting receptor-ligand dimer binds to specific DNA regulatory sequences (retinoic acid response elements, or RAREs) in the promotor regions of retinoid-responsible genes. Downstream alterations to gene expression induced by binding to these regions is the principle mechanism through which trifarotene exerts its comedolytic, anti-inflammatory, and depigmenting effects. Like other retinoids, trifarotene influences the expression of a number of genes involved in retinoid metabolism, epidermal differentiation/proliferation, and epidermal response to stress. In addition, trifarotene appears to modulate retinoid-mediated pathways involved in proteolysis, skin hydration, and cell adhesion - modulation of these additional pathways has not been observed with other retinoids and may therefore be unique to trifarotene. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Trifarotene belongs to the class of organic compounds known as m-terphenyls. These are terphenyls with a structure containing the 1,3-diphenylbenzene skeleton, classified under the direct parent group M-terphenyls. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Terphenyls subclass.

Categories:

Trifarotene is categorized under the following therapeutic classes: Alkenes, Anti-Acne Preparations, Anti-Acne Preparations for Topical Use, Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Dermatologicals, Misc. Skin and Mucous Membrane Agents, Polyenes, Retinoids, Retinoids for Topical Use in Acne. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Trifarotene include:

• Melting Point: 245C
• pKa: 5.69 (pKa1)