Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene.
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Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, Dreno B, Gamboa B, Jomard A, Luzy AP, Mauvais P, Mounier C, Pascau J, Pelisson I, Portal T, Rivier M, Rossio P, Thoreau E, Vial E, Voegel JJ
Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene.
Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4.
- PubMed ID
- 29974453 [ View in PubMed]
- Abstract
BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) gamma, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: 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. RESULTS: Trifarotene is a selective RARgamma agonist with > 20-fold selectivity over RARalpha and RARbeta. 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. CONCLUSIONS: Based on its RARgamma 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Trifarotene Retinoic acid receptor alpha Protein Humans UnknownAgonistDetails Trifarotene Retinoic acid receptor beta Protein Humans UnknownAgonistDetails Trifarotene Retinoic acid receptor gamma Protein Humans YesAgonistDetails