madman
Super Moderator
Abstract: Retinoids have numerous applications in inflammatory, dyskeratotic, and oncohematology diseases. Retinoids have now reached the fourth generation, progressively reducing toxicity whilst increasing their efficacy. Trifarotene is a new fourth-generation retinoid with a selective action on RAR-γ. In this review, we reported the trials—both concluded and in progress—including the use of trifarotene in dermatological diseases. Studies were identified by searching electronic databases (MEDLINE, EMBASE, PubMed, Cochrane, Trials.gov) from 2012 to today and reference lists of respective articles. Only articles published in the English language were included. Randomized trials evaluating trifarotene tolerability, safety, and efficacy in congenital ichthyosis and acne have demonstrated great results and mild side effects, leading to the approval by the FDA of trifarotene for the treatment of lamellar ichthyosis in 2014, and of acne vulgaris in October 2019. No high-quality randomized clinical trials have evaluated the treatment of primary cutaneous lymphomas with trifarotene. Finally, we are hypothesizing future perspectives in the treatment of non-melanoma skin cancers, fungal infections, photoaging, and hand-foot skin reactions with trifarotene.
1. Introduction
Vitamin A (or retinol, a diterpene), a cardinal micronutrient in human metabolism, is a lipophilic molecule composed of isoprene units. As an isoprenoid, it is characterized by a hydrocarbon chain containing an ending hydroxyl. The term “retinoid” concerns both natural and synthetic analogs of vitamin A. In synthetic analogs, such as etretinate, acitretin, or tazarotene, a benzene ring substitutes the cyclohexane. According to the International Union of Pure and Applied Chemistry and the International Union of Biochemistry and Molecular Biology, retinoids are characterized by four isoprene units with a head-to-tail structure [1].
It is known that vitamin A and its synthetic analogs have a crucial role in modulating some skin functions; in particular, they regulate epidermal keratinization, differentiation, maturation, and proliferation [2]. Due to all these effects, retinoids are largely used in dermato-oncology, both in treatment and chemo-prevention (non-melanoma skin cancers, primary cutaneous T-cell lymphomas), and even in the treatment of cutaneous inflammatory diseases (acne vulgaris, rosacea, melasma, post-inflammatory hyperpigmentation, mycosis) and hyperproliferative conditions (ichtyosis, psoriasis, pityriasis rubra pilaris) [2]. Moreover, they play a central role in protecting the skin from free radicals damage, as shown by their use also in photoaging. The aim of this review is to highlight the current clinical application (Figure 1) of trifarotene and future perspectives in dermatology.
2. Mechanism of Action of Vitamin A and Its Analogues
Retinoids can be classified into three generations, in respect of molecular structures and properties (Figure 2):
1. The first generation is composed of natural retinoids, obtained modifying polar groups of vitamin A, which do not act selectively: retinol and its metabolites, such as retinal, tretinoin, isotretinoin, and alitretinoin;
2. The second generation is constituted by monoaromatic retinoids, synthetic compounds where a benzene ring replaces the cyclohexene ring: etretinate, and acitretin;
3. The third generation is made up of polyaromatic retinoids, resulting from cyclization of the side chain and characterized by a selective activity towards receptor: adapalene, tazarotene, and bexarotene [16].
In the skin, RAR-γ is the most represented isoform [17], sustaining the rational use of topical RAR-γ agonists. Therefore, Thoreau and colleagues described the structure of RAR-γ ligand-binding domain, permitting the design of a novel triaryl series of agonists, which was optimized and ultimately led to trifarotene, a new fourth-generation topical retinoid [18]. Aubert and colleagues have described the preclinical pharmacological features of trifarotene [19], which has been approved for the treatment of lamellar ichthyosis, in 2014, and acne vulgaris, in October 2019, by the FDA and is currently undergoing approval even by the EMA [20,21]. Trifarotene is a strong and selective agonist of RARγ, with lower activity on RAR-β and RAR-α (16- and 65-fold, respectively), and has no activity on RXRs [19]. The binding of trifarotene on RAR-γ results in the dimerization of the receptor, leading to attach specific RAREs of retinoid-responsible genes. Downstream gene expression alterations are the principal way through which trifarotene exerts its anti-inflammatory, comedolytic, and depigmenting actions [21].
Trifarotene influences three different pathways, identified by a large-scale gene expression analysis:
1) Skin hydration: trifarotene induces skin peptidyl arginine deiminase 1 and aquaporin3 channels, and, therefore, influences skin barrier functions;
2) Cell adhesion: trifarotene weakens hemidesmosomes, reducing intercellular adhesion. The minor cohesion among keratinocytes explains its comedolytic properties;
3) Proteolysis: trifarotene downregulates matrix metalloproteinases (MMPs), which act as proteolytic enzymes on elastin and collagen, thus improving skin texture [19,22].
Ex-vivo pharmacokinetic models on trifarotene proved the high stability of the compound, with a half-life of >24 h. Despite this, it is quickly metabolized by hepatic microsomal enzymes, with a half-life of minutes, compared to tazarotenic acid, which has a 10-fold higher stability in hepatic microsomes. This is a predictor of a favorable safety profile. The metabolism of trifarotene is catalyzed primarily by cytochrome (CY) P2C9, CYP3A4, CYP2C8, and, to a lesser extent, by CYP2B6 [18].
4. Trifarotene Properties and Current Applications in Dermatology
4.1. RAR-γ Selectivity
4.2. Trifarotene Safety and Tolerability
4.3. Current Applications in Dermatology
Herein we illustrate the rational use of trifarotene in skin diseases.
4.3.1. Acne Vulgaris
4.3.2. Autosomal Recessive Congenital Ichthyosis
4.3.3. Primary Cutaneous T-Cell Lymphoma
5. Perspectives
5.1. Non-Melanoma Skin Cancer
5.2. Invasive Fungal Infection (IFI)
5.3. Skin and Nail Mycosis
5.4. Photoaging
5.5. Hand-Foot Skin Reaction
6. Conclusions
Retinoids are largely applied in cutaneous inflammatory, dyskeratotic, and infectious diseases, besides oncohematology. In this review, we have focused our attention, particularly on trifarotene, a new fourth-generation retinoid with a selective action on RAR-γ. Trifarotene has been tested for the treatment of acne and congenital ichthyosis, demonstrating its safety and tolerability. No high-quality randomized clinical trials are currently evaluating the treatment of primary cutaneous lymphomas with trifarotene. Differently from other retinoids, trifarotene acts selectively on RAR-γ reducing RAR-β adverse effects, and offer a more favorable clinical profile compared to the drugs with dual action on both RAR-β and RAR-γ, such as tretinoin and derivatives. As RAR-γ is much more abundant then the other retinoids receptors in the skin, this could be the rationale for increasing studies on trifarotene usage in skin disorders, as already seen with the previous generation retinoids.
1. Introduction
Vitamin A (or retinol, a diterpene), a cardinal micronutrient in human metabolism, is a lipophilic molecule composed of isoprene units. As an isoprenoid, it is characterized by a hydrocarbon chain containing an ending hydroxyl. The term “retinoid” concerns both natural and synthetic analogs of vitamin A. In synthetic analogs, such as etretinate, acitretin, or tazarotene, a benzene ring substitutes the cyclohexane. According to the International Union of Pure and Applied Chemistry and the International Union of Biochemistry and Molecular Biology, retinoids are characterized by four isoprene units with a head-to-tail structure [1].
It is known that vitamin A and its synthetic analogs have a crucial role in modulating some skin functions; in particular, they regulate epidermal keratinization, differentiation, maturation, and proliferation [2]. Due to all these effects, retinoids are largely used in dermato-oncology, both in treatment and chemo-prevention (non-melanoma skin cancers, primary cutaneous T-cell lymphomas), and even in the treatment of cutaneous inflammatory diseases (acne vulgaris, rosacea, melasma, post-inflammatory hyperpigmentation, mycosis) and hyperproliferative conditions (ichtyosis, psoriasis, pityriasis rubra pilaris) [2]. Moreover, they play a central role in protecting the skin from free radicals damage, as shown by their use also in photoaging. The aim of this review is to highlight the current clinical application (Figure 1) of trifarotene and future perspectives in dermatology.
2. Mechanism of Action of Vitamin A and Its Analogues
Retinoids can be classified into three generations, in respect of molecular structures and properties (Figure 2):
1. The first generation is composed of natural retinoids, obtained modifying polar groups of vitamin A, which do not act selectively: retinol and its metabolites, such as retinal, tretinoin, isotretinoin, and alitretinoin;
2. The second generation is constituted by monoaromatic retinoids, synthetic compounds where a benzene ring replaces the cyclohexene ring: etretinate, and acitretin;
3. The third generation is made up of polyaromatic retinoids, resulting from cyclization of the side chain and characterized by a selective activity towards receptor: adapalene, tazarotene, and bexarotene [16].
In the skin, RAR-γ is the most represented isoform [17], sustaining the rational use of topical RAR-γ agonists. Therefore, Thoreau and colleagues described the structure of RAR-γ ligand-binding domain, permitting the design of a novel triaryl series of agonists, which was optimized and ultimately led to trifarotene, a new fourth-generation topical retinoid [18]. Aubert and colleagues have described the preclinical pharmacological features of trifarotene [19], which has been approved for the treatment of lamellar ichthyosis, in 2014, and acne vulgaris, in October 2019, by the FDA and is currently undergoing approval even by the EMA [20,21]. Trifarotene is a strong and selective agonist of RARγ, with lower activity on RAR-β and RAR-α (16- and 65-fold, respectively), and has no activity on RXRs [19]. The binding of trifarotene on RAR-γ results in the dimerization of the receptor, leading to attach specific RAREs of retinoid-responsible genes. Downstream gene expression alterations are the principal way through which trifarotene exerts its anti-inflammatory, comedolytic, and depigmenting actions [21].
Trifarotene influences three different pathways, identified by a large-scale gene expression analysis:
1) Skin hydration: trifarotene induces skin peptidyl arginine deiminase 1 and aquaporin3 channels, and, therefore, influences skin barrier functions;
2) Cell adhesion: trifarotene weakens hemidesmosomes, reducing intercellular adhesion. The minor cohesion among keratinocytes explains its comedolytic properties;
3) Proteolysis: trifarotene downregulates matrix metalloproteinases (MMPs), which act as proteolytic enzymes on elastin and collagen, thus improving skin texture [19,22].
Ex-vivo pharmacokinetic models on trifarotene proved the high stability of the compound, with a half-life of >24 h. Despite this, it is quickly metabolized by hepatic microsomal enzymes, with a half-life of minutes, compared to tazarotenic acid, which has a 10-fold higher stability in hepatic microsomes. This is a predictor of a favorable safety profile. The metabolism of trifarotene is catalyzed primarily by cytochrome (CY) P2C9, CYP3A4, CYP2C8, and, to a lesser extent, by CYP2B6 [18].
4. Trifarotene Properties and Current Applications in Dermatology
4.1. RAR-γ Selectivity
4.2. Trifarotene Safety and Tolerability
4.3. Current Applications in Dermatology
Herein we illustrate the rational use of trifarotene in skin diseases.
4.3.1. Acne Vulgaris
4.3.2. Autosomal Recessive Congenital Ichthyosis
4.3.3. Primary Cutaneous T-Cell Lymphoma
5. Perspectives
5.1. Non-Melanoma Skin Cancer
5.2. Invasive Fungal Infection (IFI)
5.3. Skin and Nail Mycosis
5.4. Photoaging
5.5. Hand-Foot Skin Reaction
6. Conclusions
Retinoids are largely applied in cutaneous inflammatory, dyskeratotic, and infectious diseases, besides oncohematology. In this review, we have focused our attention, particularly on trifarotene, a new fourth-generation retinoid with a selective action on RAR-γ. Trifarotene has been tested for the treatment of acne and congenital ichthyosis, demonstrating its safety and tolerability. No high-quality randomized clinical trials are currently evaluating the treatment of primary cutaneous lymphomas with trifarotene. Differently from other retinoids, trifarotene acts selectively on RAR-γ reducing RAR-β adverse effects, and offer a more favorable clinical profile compared to the drugs with dual action on both RAR-β and RAR-γ, such as tretinoin and derivatives. As RAR-γ is much more abundant then the other retinoids receptors in the skin, this could be the rationale for increasing studies on trifarotene usage in skin disorders, as already seen with the previous generation retinoids.
