Aklief Mechanism of Action

Pharmacology: Pharmacodynamics: At the approved recommended dosage, Trifarotene (Aklief) Cream does not prolong the QT interval to any clinically relevant extent.
Mechanism of Action: 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.
Pharmacokinetics: Pharmacokinetics of trifarotene was evaluated in adults and children (10-17 years old) with acne vulgaris following once daily application of Trifarotene (Aklief) 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 at steady state were quantifiable in 7 of 19 adult patients (37%) after 4 weeks of treatment. 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 three out of seventeen (18 %) children, systemic exposure was quantifiable. C_max ranged from below the limit of quantification (LOQ less than 5 pg/mL) to 9 pg/mL and AUC_0-24h ranged from 89 to 106 pg*.h/mL.
After 2 weeks of topical application, both adults and children achieved a steady-state drug concentration.
No drug accumulation is expected with long-term use in both adults and pediatric patients.
Overall, systemic exposure levels were low and similar in adults and children.
Distribution: Trifarotene penetrates the skin with an exponential distribution from the stratum corneum to the epidermis and dermis. Plasma protein binding is approximately 99.9%.
Significant binding of trifarotene to red blood cells was not observed.
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.
Drug Interactions Studies: Clinical Studies and Model-Based Approaches: No clinically significant differences in the pharmacokinetics of the trifarotene were predicted when used concomitantly with fluconazole (a moderate CYP2C9 and CYP3A inhibitor).
In Vitro Studies: Cytochrome P450 (CYP) Enzymes: AKLIEF Cream is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, or induce CYP1A2, 2B6, and 3A4.
Transporter Systems: Trifarotene (Aklief) Cream is not expected to inhibit MATE, OATP, OAT, OCT, BCRP, Pgp, BSEP, or MRP.