Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study

Abstract

Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts. Generally, plasma exposure was greater with the 2% cream and decreased from day 1 to day 21. Median T ranged from 1 to 4 hours. Preliminary efficacy results were similar between the 1% and 2% concentrations, with the 1% cream showing better tolerability based on 3 subjects in the 2% cohort who discontinued treatment because of systemic AEs. The efficacy and safety of 1% tapinarof support results of previous positive studies that used a different formulation. However, conclusions in the present study are limited because of the open-label design and small number of participants. The 1% cream was selected as the concentration for use in future studies because of its lower AE incidence and efficacy comparable to the 2% cream.

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

“…Coal tar, glyteer, and tapinarof could feasibly upregulate the EDC molecules, including FLG, IVL, and hornerin, via AHR activation and exert their antioxidative function via NRF2 activation [25,31,152]. Recent clinical trials of topical tapinarof have proved its efficacy for AD compared with placebo control [150,151,156]. Medicinal AHR/NRF2 dual agonists can restore the IL-4/IL-13-STAT6-induced downregulation of FLG, LOR, and IVL expression.…”

Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis

“…Tapinarof is a high affinity AHR ligand with antioxidative activity via NRF2 activation and a ROS-scavenging structure [102] (Figure 1). Tapinarof has gained increased attention because its topical application is efficacious for patients with AD in clinical trials [21,100,104]. Tapinarof activates the AHR/CYP1A1 axis and augments the expression of filaggrin and involucrin [102].…”

“…Tapinarof activates the AHR/CYP1A1 axis and augments the expression of filaggrin and involucrin [102]. Even in barrier-disrupted AD patients, systemic absorption of topical tapinarof is limited and likely decreases during the treatment course in parallel with treatment success that restores the barrier dysfunction [104]. In general, topical tapinarof is tolerable but frequent adverse events include headaches and folliculitis [104].…”

Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis

“…Tapinarof activates both AHR and NRF2, up-regulates the expression of FLG and IVL, and exhibits antioxidative activity [209,210]. Double-blind clinical trials have shown that topical tapinarof is efficacious for treating patients with AD compared with placebo [211][212][213].…”