Clinical Pharmacology and Safety of Trifarotene, a First-in-Class RARγ-Selective Topical Retinoid

Abstract

Trifarotene is a new drug with retinoic acid receptor activity and selectivity for retinoic acid receptor-γ. The reported studies aimed at assessing the clinical pharmacology and safety of trifarotene. The clinical pharmacology of topical trifarotene up to 100 µg/g was extensively investigated through 2 maximal usage pharmacokinetic trials (MUsT) conducted in adult (≥18 years) and pediatric patients (9-17 years) with moderate to severe acne and two studies conducted in healthy volunteers: 1 thorough QT_C study and 1 drug-drug interaction study with concomitantly administered oral levonorgestrel (0.15 mg)/ethinyl estradiol (0.03 mg). Safety assessments included adverse event reporting and assessment of erythema, scaling, dryness, and stinging/burning using a scale from 0 = none to 4 = severe, as well as the evaluation of the systemic safety of trifarotene through routine laboratory testing. Systemic absorption of trifarotene was generally unquantifiable in the target population, especially when applied at 50 µg/g. QT_C investigations did not show any risk of cardiovascular health issues; trifarotene did not reduce the systemic exposure to oral contraceptives such as levonorgestrel/ethinyl estradiol. Safety analyses did not show local or systemic safety concerns with trifarotene up 100 µg/g, a dose twice as high as the intended market dose. Results showed that trifarotene 50 µg/g cream is well tolerated and safe, even when applied under maximized conditions in adults and pediatric acne patients presenting with severe acne. Daily use of trifarotene 50 µg/g cream was not associated with cardiovascular effects and did not result in drug-drug interaction in women of childbearing potential using oral contraception.

Keywords: MUsT; TQC study; drug-drug interaction; pharmacokinetics; trifarotene.

Figure 1

Adult MUsT (MUsT 1): Individual plasma profiles on day 29 for (A) trifarotene 50 µg/g cream (7/19 quantifiable subjects) and (B) trifarotene 100‐µg/g cream (11/18 quantifiable subjects). Pediatric MUsT (MUsT 2): Individual plasma profiles on day 29 for (C) trifarotene 50 µg/g cream (3/17 quantifiable subjects) and (C) trifarotene 100‐µg/g cream (11/16 quantifiable subjects). Note the 72‐hour time point was excluded from the figure because all plasma concentrations were nonquantifiable. Nonquantifiable data were replaced by the LLOQ (ie, 5 pg/mL). LLOQ, lower level of quantification; MUsT, maximal usage pharmacokinetic trial.

Figure 2

TQT study: Concentration response relationship.

Figure 3

Drug‐drug interaction study: EE (A) and LNG (B) mean (SD) trifarotene plasma concentration profiles per treatment day (linear scale). EE, ethinyl estradiol; LNG, levonorgestrel; SD, standard deviation.

Figure 4

Drug‐drug interaction study: Trifarotene individual plasma concentrations vs time on day 18 (linear scale, LOQ: 5 pg/mL); 6 quantifiable subjects of 22; nonquantifiable data were replaced by the lower level of quantification (ie, 5 pg/mL). LOQ, level of quantification.