Research Department, Galderma R&D, Les Templiers, 2400 Route des Colles, 06410, Biot, France.
Department of Dermatology, Nantes University Hospital, Nantes, France.
Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4.
First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum.
To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene.
In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established.
Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARβ. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream.
Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.
第一代和第三代维 A 酸是痤疮的主要治疗药物。尽管它们有效，但对表皮和漏斗部表达的维 A 酸受体 (RAR) γ 的选择性不完全。
描述新型维 A 酸三芳维 A 酸的体外代谢和药理学特性。
体外测定了 RAR 的疗效、效价和选择性，以及对人角质形成细胞和离体培养皮肤中维 A 酸靶基因表达的活性。体内研究了局部去角质、抗炎和脱色作用。研究了三芳维 A 酸在痤疮非皮损皮肤中的基因表达谱，并与离体和体内模型进行了比较。最后，还在人角质形成细胞和肝微粒体中建立了三芳维 A 酸的代谢稳定性。
三芳维 A 酸是一种选择性 RARγ 激动剂，对 RARα 和 RARβ 的选择性>20 倍。三芳维 A 酸在角质形成细胞中具有活性和稳定性，但在人肝微粒体中迅速代谢，预示着安全性提高。在体内，0.01%三芳维 A 酸局部应用具有高度的去角质作用，具有抗炎和脱色作用。基因表达研究表明，在离体和体内模型以及 0.005%三芳维 A 酸乳膏局部应用 4 周后，其可有效激活已知的维 A 酸调节过程（表皮分化、增殖、应激反应、维 A 酸代谢）和新途径（蛋白水解、转运/皮肤水合、细胞黏附）。
基于其 RARγ 选择性、在人肝微粒体中的快速降解以及包括有效调节表皮过程在内的药理学特性，局部应用三芳维 A 酸可能具有良好的疗效，并且在痤疮和鱼鳞癣性疾病中可能具有良好的安全性。
