Differin Mechanism of Action

Pharmacology: Cream: Adapalene is a retinoid-like compound which, in in vivo and in vitro models of inflammation, has been demonstrated to possess anti-inflammatory properties; Adapalene is essentially stable to oxygen and light and is chemically non-reactive. Mechanistically, adapalene binds like tretinoin to specific retinoic acid nuclear receptors but, unlike tretinoin, not to cytosolic receptor binding proteins. Adapalene applied cutaneously is comedolytic in the rhino mouse model and also has effects on the abnormal processes of epidermal keratinization and differentiation, both of which are present in the pathogenesis of acne vulgaris. The mode of action of adapalene is suggested to be a normalisation of differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Adapalene is superior to reference retinoids in standard anti-inflammatory assays, both in vivo and in vitro. Mechanistically, it inhibits chemotactic and chemokinetic responses of human polymorphonuclear leucocytes and also the metabolism by lipoxidation of arachidonic acid to pro-inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne may be modified by adapalene. Studies in human patients provide clinical evidence that cutaneous adapalene is effective in reducing the inflammatory components of acne (papules and pustules).
Absorption of adapalene through human skin is low; in clinical trials measurable plasma adapalene levels were not found following chronic cutaneous application to large areas of acneic skin with an analytical sensitivity of 0.15 ng.mL-1. After administration of [14C]-adapalene in rats (IV, IP, oral and cutaneous), rabbits (IV, oral and cutaneous) and dogs (IV and oral), radioactivity was distributed in several tissues, the highest levels being found in liver, spleen, adrenals and ovaries. Metabolism in animals has been tentatively identified as being mainly by O-demethylation, hydroxylation and conjugation, and excretion is primarily by the biliary route.
In animal studies, adapalene was well tolerated on cutaneous application for periods of up to six months in rabbits and for up to two years in mice. The major symptoms of toxicity found in all animal species by the oral route were related to hypervitaminosis A syndrome, and included bone dissolution, elevated alkaline phosphatase and a slight anaemia. Large oral doses of adapalene produced no adverse neurological, cardiovascular or respiratory effects in animals. Adapalene is not mutagenic. Lifetime studies with adapalene have been completed in mice at cutaneous doses of 0.6, 2 and 6 mg.kg-1.d-1 and in rats at oral doses of 0.15, 0.5 and 1.5 mg.kg-1.d-1.
The only significant finding was a statistically significant increase of benign phaeochromocytomas of the adrenal medulla among male rats receiving adapalene at 1.5 mg.kg-1.d-1. These changes are considered to have no relevance to the cutaneous use of adapalene.
Pharmacodynamics: Adapalene is a chemically stable, naphthoic acid derivative with retinoid-like activity. Biochemical and pharmacological profile studies have demonstrated that adapalene acts in the pathology of Acne vulgaris: it is a potent modulator of cellular differentiation and keratinisation and it has anti-inflammatory properties. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors. Current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models; it also inhibits the metabolism of arachidonic acid to inflammatory mediators. In vitro studies have shown inhibition of the AP-1 factors and the inhibition of the expression of toll like receptors 2. This profile suggests that the cell mediated inflammatory component of acne is reduced by adapalene.
The clinical significance of these findings for the mitigation of facial photoaging is unknown.
Pharmacokinetics: A pharmacokinetic trial was conducted in 50 adults with acne vulgaris who were treated with once-daily applications during a 4-week period with 2 grams/day of Adapalene (Differin) 0.1 % GEL or Adapalene (Differin) 0.3 % GEL applied as a thin layer to the face, shoulders, upper chest and upper back.
Over the 4-week treatment with Adapalene (Differin) 0.1 % GEL, only 4 to 7 subjects out of 25 had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.04 ± 0.08 ng/mL and a mean AUC0-24h of 0.50 ± 0.99 ng.h/mL The most exposed subject had adapalene Cmax and AUC0-24h of 0.31 ng/mL and 3.47 ng.h/mL, respectively.
Over the 4-week treatment with Adapalene (Differin) 0.3 % GEL, 20 to 22 subjects out of 25 had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.18 ± 0.09 ng/mL and a mean AUC0-24h of 2.84 ± 1.75 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.40 ng/mL and 5.99 ng.h/mL, respectively.
Similar results were observed in adult and adolescent subjects (12 years of age and older) with acne vulgaris who were treated with once-daily applications during a 4-week period with, on average, 1.95 grams/day (range 1.2 - 2.9 grams/day) of Differin 0.1 % gel or with on average, 2.3 grams/day (range 1.4 - 3.2 grams/day) of Differin 0.3 % gel applied as a thin layer to the face, shoulders, upper chest and upper back.
Over the 4-week treatment with Adapalene (Differin) 0.1 % GEL in 24 adult and adolescent subjects (12 years of age and older) with moderate to severe acne vulgaris, all the subjects had quantifiable adapalene plasma concentrations above the limit of quantification of 0.02 ng/mL at steady state, with a mean Cmax of 0.05 ± 0.03 ng/mL and a mean AUC0-24h of 0.87 ± 0.43 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.17 ng/mL and 2.90 ng.h/mL, respectively.
Over the 4-week treatment with Adapalene (Differin) 0.3 % GEL in 30 adult and adolescent subjects (12 years of age and older) with severe acne vulgaris, 14 to 16 subjects had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL at steady state, with a mean Cmax of 0.15 ± 0.08 ng/mL and a mean AUC0-24h of 2.47 ± 1.31 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h of 0.46 ng/mL and 7.40 ng.h/mL, respectively.
Excretion of adapalene appears to be primarily by the biliary route.