Trifarotene

Trifarotene is an agonist of retinoic acid receptors (RAR), with particular activity at the gamma subtype of RAR. Stimulation of RAR results in modulation of target genes which are associated with various processes, including cell differentiation and mediation of inflammation. The exact process by which trifarotene ameliorates acne is unknown.

At the approved recommended dosage, trifarotene cream does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics of trifarotene was evaluated in a study involving 19 adult subjects with acne vulgaris following once daily application of trifarotene cream for 29 days (daily dose range 1.5 g/day to 2 g/day) to the face, shoulders, chest and upper back.

Absorption

Systemic concentrations were at steady state following 2 weeks of treatment and were quantifiable in 7 subjects. Steady state C_max ranged from below the limit of quantification (less than 5 pg/mL) to 10 pg/mL and AUC_0-24h ranged from 75 to 104 pg.h/mL in adults. No drug accumulation is expected with long-term use.

Distribution

Plasma protein binding is approximately 99.9%

Elimination

The terminal half-life ranged from 2 to 9 hours.

Metabolism

Trifarotene is primarily metabolized by CYP2C9, CYP3A4, CYP2C8, and to a lesser extent by CYP2B6 in vitro.

Excretion

Trifarotene is primarily excreted by the feces.

Specific Populations

Pediatric Patients

Steady state C_max ranged from less than 5 pg/mL to 9 pg/mL and AUC_0-24h ranged from 89 to 106 pg.h/mL in pediatrics (10 to 17-years-old). Steady state conditions were achieved in patients following 2 weeks of topical administration. No drug accumulation is expected with long-term use.

Drug Interactions Studies

Clinical Studies and Model-Based Approaches

No clinically significant differences in the pharmacokinetics of trifarotene were predicted when used concomitantly with fluconazole (a moderate CYP2C9 and CYP3A inhibitor).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: trifarotene cream is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, or induce CYP1A2, 2B6, and 3A4.

Transporter Systems: trifarotene cream is not expected to inhibit MATE, OATP, OAT, OCT, BCRP, P-gp, BSEP, or MRP.