BackgroundFirst- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) , expressed in the epidermis and infundibulum. ObjectivesTo characterize the invitro metabolism and the pharmacology of the novel retinoid trifarotene. Materials and methodsIn 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 exvivo 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 exvivo and invivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. ResultsTrifarotene is a selective RAR agonist with >20-fold selectivity over RAR and RAR. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0<bold></bold>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 exvivo and invivo models, as well as in human skin after 4weeks of topical application of trifarotene 0<bold></bold>005% cream. ConclusionsBased on its RAR 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. What's already known about this topic? All-trans and 13-cis retinoic acid, which binds all three retinoic acid receptors (RARs), and adapalene and tazarotene, which interact preferentially with RAR and RAR, are first-line treatments for acne and are also used in other inflammatory skin diseases. Topical formulations of these retinoids avoid significant systemic retinoid-related side-effects. What does this study add? Trifarotene is the first fourth-generation retinoid with potent and selective RAR agonist activity, potentially associated with an improved efficacy/safety ratio compared with less selective RAR agonists. The pharmacological potency of trifarotene translates from invitro models to topically treated rodent and human skin invivo. The modulated pathways collectively are expected to translate into strong clinical efficacy in acne. Based on its rapid degradation in human hepatic microsomes, trifarotene is expected to be rapidly eliminated in the blood stream, thereby potentially providing good safety, which should be particularly useful for the treatment of patients with ichthyosis with application on large surface areas. Based on the favourable metabolic and pharmacological characteristics of trifarotene, it is worth investigating the clinical efficacy of this fourth-generation retinoid in acne and lamellar ichthyosis. Linked Editorial:Balak. Br J Dermatol 2018; 179:231-232. Plain language summary available online Respond to this article