Trifarotene – A brief review in dermatology

HISTORY AND INTRODUCTION

Tretinoin 0.05% solution (also known as all-trans retinoic acid [ATRA]; Vitamin A acid) was approved by the US Food and Drug Administration (FDA) in 1971 for the treatment of acne vulgaris and was the first topical retinoid. Poor adherence has been linked to the local irritation brought on by topical retinoids, which is particularly noticeable during the first few weeks of therapy. To increase efficacy and tolerability, new retinoids, formulations, and combinations were released in the years that followed. Over 50 years of study has produced new generations of retinoids that are more tolerable and have better stability (mostly due to structural modifications). Trifarotene is the only fourth-generation retinoid, which is selectively bound to the retinoic acid receptor-gamma (RAR-g) receptor. In 2019, the FDA approved trifarotene, the first topical retinoid of its kind, for the treatment of acne vulgaris in patients who are 9 years of age or older.^[1]

However, larger human studies and multiple perspectives of the drug are to be tested to assess its efficacy in other dermatological indications.

STRUCTURE

The intranuclear RAR or retinoic X receptor, each of which has three primary isotypes (alpha, beta, and gamma), represents the way retinoids exert their actions. The FDA has approved four topical preparations for the treatment of acne vulgaris: ATRA, often known as tretinoin (first generation), adapalene and tazarotene (third generation), and trifarotene (fourth generation). In the epidermis, RAR-g is the most prevalent isoform. Trifarotene is the only topical retinoid that binds to it selectively.^[1]

MECHANISM OF ACTION AND PHARMACOKINETICS

Mechanisms that have not been linked to other retinoids before, such as:

1. Cell adhesion: Trifarotene decreases dystonin, which weakens intercellular adhesions and hemidesmosomes and permits comedolysis and keratinocyte migration

2. Skin hydration: Trifarotene affects skin barrier function and improves cutaneous hydration by upregulating aquaporin 3 and peptidyl arginine deiminase 1

3. Proteolysis: Trifarotene efficiently promotes antiaging advantages in the skin by downregulating matrix metalloproteinases, which are proteins that break down collagen and elastin.

Ex vivo human keratinocytes have shown that trifarotene is very metabolically stable (>24 h), while hepatic microsomes rapidly metabolize it (half-life <5 min), leading to significant cutaneous activity and low systemic concentrations.

When administering trifarotene to large body surface regions, as in truncal acne, it is necessary for the liver to eliminate the medicine quickly. This minimizes potential safety concerns related to systemic absorption. Despite repeated administrations, its short half-life (2–9 h) prevented systemic accumulation. There were no hematologic or biochemical anomalies found.

METHOD OF APPLICATION

Providing the patient with instructions on how to apply trifarotene is crucial to reduce the chances of side effects. Before the treatment, the affected areas should be washed and pat dried using a light or soapless cleaner. The next step is to apply a thin coating of trifarotene cream in the evening. One pump for the face and two pumps for the chest, shoulders, and back are advised to ensure consistency. One can use moisturizer as often as necessary to reduce irritation and dryness. Sunscreen application is advised daytime.^[2]

To date, every published study has looked at the use of trifarotene as a monotherapy and in a cream formulation with a single strength of 50 ìg/g. Other topical retinoids are available in cream and gel formulations; therefore, future research examining different trifarotene formulations ought to be taken into consideration. Trifarotene cream use may be limited in cases with oily skin, which is a prevalent phenotype among acne patients and for which gel formulations are often recommended.^[3]

GENETIC AND MOLECULAR PATHWAY OF TRIFAROTENE

A distinct group of 67 genes were modified by trifarotene, the most dominantly regulated of which were MMP12 and MMP13, CXCL13, XCL1, and SPP1/Osteopontin. Trifarotene affected T-cell migration, neutrophil chemotaxis, and proinflammatory responses. It also has a decrease in B-cells; in acne, larger B-cell counts have been linked to more severe cases of the condition.^[4]

INDICATIONS

CONCLUSION

While research on mice has demonstrated that trifarotene has a stronger comedolytic impact than tazarotene and ATRA, no human studies have been conducted to support these results in clinical settings. Trifarotene’s extremely selective activity, which may lower the likelihood of discomfort, makes it distinctive. Trifarotene’s known side effect profile, however, appears to be comparable to other retinoids’. There are currently no comparison studies that demonstrate trifarotene’s advantages in terms of side effects. According to the literature, retinoid’s irritability is an extension of their therapeutic benefit. We still do not know if trifarotene’s claims of reduced irritability are clinically meaningful or if efficacy suffers as a result. Hence, comparative human study should be conducted to establish its efficacy and safety as compared to other topical retinoids.