Differin

Differin Mechanism of Action

adapalene

Manufacturer:

Galderma

Distributor:

Zuellig
Full Prescribing Info
Action
ATC Code: D10AD03.
Pharmacology: Gel 0.1% and 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 normalization 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 a hypervitaminosis A syndrome, and included bone dissolution, elevated alkaline phosphatase and a slight anemia. 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.
Gel 0.3%: Pharmacodynamics: Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). 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, by lipoxidation, to inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).
Mechanism of Action: Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Clinical Trials: Study demographics and trial design: See Table 1.

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Male and female subjects, 12 years of age or older, were eligible to enroll in this controlled clinical trial. In study RD.06.SRE.18081, subjects with acne vulgaris with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions and no nodules or cysts were eligible to enroll in this study. (See Table 2.)

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Male and female subjects, 12 years of age or older, were eligible to enroll in this controlled clinical trial. In study RD.03.SRE.2673, subjects with acne vulgaris with 15 to 50 inflammatory and 30 to 200 non-inflammatory lesions and a maximum of two nodules/cysts were eligible to enroll in this study.
Study results: See Tables 3 and 4.

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Pharmacokinetics: See Table 5.

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Absorption: Absorption of adapalene through human skin is low. No quantifiable levels of parent substance have been found in the plasma of patients following chronic adapalene gel 0.1% application in controlled clinical trials (limit of quantification = 0.25 ng/mL). In adult patients with acne vulgaris who received daily applications of 0.3% gel for 10 days, the mean AUC(0-24h) on Day 10 was 8.94 ngAh/mL (SD: 8.99) and the mean Cmax was 0.553 ng/mL (SD: 0.466). The Cmax ranged from < 0.1 to 2 ng/mL and the maximum AUC(0-24h) value obtained was 36.1 ngAh/mL. The terminal apparent half-life ranged from 13 to 16 hours, thereby indicating that a pharmacokinetic steady-state was reached before Day 10.
Distribution: Classical plasma protein binding techniques were not feasible for adapalene due to the physiochemical properties of the molecule. However, an alternative method was adopted which measures the partitioning of the drug between plasma or protein solutions and erythrocytes. When 3H-adapalene was incubated with human whole blood, 26% was bound to erythrocytes and total binding of adapalene in blood was > 99%. Adapalene bound primarily to lipoproteins and human serum albumin.
Metabolism: Following 24-hour incubation with human hepatocytes, more than 90% of adapalene has been metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfatation.
Excretion: Excretion appears to be primarily by the biliary route. The majority of an administered dose of 0.3% gel was excreted by 144 hours post dose and no drug was detected after the 6th day following last application. Under maximized conditions, the mean total unchanged drug substance excreted in the faeces was 0.07% ± 0.06% of the total dose applied (range, 0.02% to 0.19%).
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