Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene
| Autor: | Johannes Voegel, B. Gamboa, Jonathan Pascau, Sophie Deret, A.P. Luzy, A. Jomard, David Piwnica, S. Blanchet‐Réthoré, P. Mauvais, T. Portal, B. Bertino, I. Pelisson, Etienne Thoreau, Patricia Rossio, E. Vial, M. Rivier, Brigitte Dréno, C. Mounier, J. Aubert, I. Carlavan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Keratinocytes medicine.drug_class Receptors Retinoic Acid Biopsy Drug Evaluation Preclinical Gene Expression Human skin Skin Pigmentation Dermatology Pharmacology Administration Cutaneous Cell Line Tissue Culture Techniques 030207 dermatology & venereal diseases 03 medical and health sciences Mice Retinoids 0302 clinical medicine Drug Stability In vivo Acne Vulgaris medicine Animals Humans Retinoid Receptor Skin Chemistry Gene Expression Profiling In vitro toxicology Cell Differentiation Retinoic acid receptor Disease Models Animal 030104 developmental biology Microsomes Liver Dermatologic Agents Ex vivo |
| Zdroj: | The British journal of dermatology. 179(2) |
| ISSN: | 1365-2133 |
| Popis: | Background 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. 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 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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