In remodeling human skin (RHE), trifarotene (CD5789) (3.3 μL 0.33 cm2; 24 hours) is involved in keratinization, desquamation, epidermalization, and cellular labeling. The average EC50 of all combined target genes for trifarotene is 0.0048% [2].

It has been demonstrated that trifarotene (0.001%-0.01% in cream, 25 mg per mouse) is completely efficacious (98% decrease) when administered at 0.01% in comedogenic dosages [2].

Animal/Disease Models: Rhino mouse[2]
Doses: 0.001%, 0.0025%, 0.005% and 0.01% cream, the dose is 25 mg/mouse (5 cm2 surface of back skin, calculated as 5 mg/cm2) one time/day; 11 days
Experimental Results: Epidermal thickness increased by 275% (66 μm) and transepidermal water loss (TEWL) increased by 285% (26 g/h/m2).

Absorption, Distribution and Excretion
Systemic absorption of trifarotene is minimal. In a pharmacokinetic study involving 19 subjects, systemic concentrations were only quantifiable in 7 - steady state Cmax values ranged from undetectable (<5 pg/mL) to 10 pg/mL and AUC0-24h ranged from 75 to 104 pg.h/mL.
Trifarotene is eliminated primarily in the feces.

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Metabolism / Metabolites
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.

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Biological Half-Life
The terminal half-life of trifarotene is typically between 2 to 9 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Trifarotene has not been studied during breastfeeding. Because it is poorly absorbed after topical application, it is a low risk to the nursing infant. Do not apply trifarotene cream directly to the nipple and areola and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Trifarotene is 99.9% protein bound in plasma.

[1]. Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1736-1741.

[2]. Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456.

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 [vitamin A], though later generation retinoids such as trifarotene and [adapalene] 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.
Trifarotene is a Retinoid.
Trifarotene is a selective retinoic acid receptor gamma (RAR gamma) agonist that can be used in the treatment of acne vulgaris. Upon topical application, trifarotene selectively binds to the RAR gamma receptor, thereby altering the expression of certain genes that are involved in inflammation and cellular differentiation.

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Drug Indication
Trifarotene is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.
Treatment of ichthyoses
Treatment of acne

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Mechanism of Action
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.

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Pharmacodynamics
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.

C29H33NO4

459.586

459.24

895542-09-3

895542-09-3;

11518241

White to off-white solid powder

1.2±0.1 g/cm3

641.9±55.0 °C at 760 mmHg

245C

342.0±31.5 °C

0.0±2.0 mmHg at 25°C

1.599

6.27

2

5

8

34

647

0

MFBCDACCJCDGBA-UHFFFAOYSA-N

InChI=1S/C29H33NO4/c1-29(2,3)25-19-23(10-12-26(25)30-14-4-5-15-30)24-18-22(11-13-27(24)34-17-16-31)20-6-8-21(9-7-20)28(32)33/h6-13,18-19,31H,4-5,14-17H2,1-3H3,(H,32,33)

3''-(tert-butyl)-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1'

CD5789 CD-5789 CD 5789

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~543.97 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)