Epiduo Mechanism of Action

Pharmacotherapeutic group: Anti-Acne Preparations for Topical Use. ATC code: D10AD53.
Pharmacology: Pharmacodynamics: Mechanism of action and Pharmacodynamic effects: EPIDUO combines two active substances which act through different, but complementary, mechanisms of action.
Adapalene: 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.
Benzoyl peroxide: Benzoyl peroxide has been shown to have antimicrobial activity; particularly against P. acnes, which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
Benzoyl peroxide is also sebostatic, counteracting the excessive sebum production associated with acne.
Clinical efficacy of Epiduo in patients aged 12 years and older: The safety and efficacy of EPIDUO applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing EPIDUO to its individual active components, adapalene and benzoyl peroxide, and to the gel vehicle in acne patients. A total of 2185 patients were enrolled in Study 1 and Study 2. The distribution of patients in the two studies was approximately 49% male and 51 % female, 12 years of age or older (mean age: 18.3 years; range 12-50), presenting 12 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions at baseline. The patients treated the face and other acne affected areas as needed once daily in the evening.
The efficacy criteria were: Success rate, percentage of patients rated 'Clear' and 'Almost Clear' at Week 12 based on the Investigator's Global Assessment (IGA);
Change and Percent Change from baseline at Week 12 in: lnflammatory lesion counts; Non-inflammatory lesion counts; Total lesion count.
The efficacy results are presented for each study in Table 1 and combined results in Table 2. EPIDUO was shown to be more effective compared to its monads and gel vehicle in both studies. Overall, the net beneficial effect (active minus vehicle) obtained from EPIDUO was greater than the sum of the net benefits obtained from the individual components, thus indicating a potentiation of the therapeutic activities of these substances when used in a fixed-dose combination. An early treatment effect of EPIDUO was consistently observed in Study 1 and Study 2 for Inflammatory Lesions at Week 1 of treatment. Non-inflammatory lesions (open and closed comedones) noticeably responded between the first and fourth week of treatment. The benefit on nodules in acne has not been established. (See Tables 1 and 2.)

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Clinical efficacy of Epiduo in children 9 to 11 years old: During a paediatric clinical trial, 285 children with acne vulgaris, aged 9 - 11 years (53% of the subjects were 11 years old, 33% were 10 years old and 14% were 9 years old) with a score of 3 (moderate) on the IGA scale and a minimum of 20 but not more than 100 total lesions (Non-inflammatory and/or Inflammatory) on the face (including the nose) at baseline were treated with Epiduo Gel once daily for 12 weeks.
The study concludes that the efficacy and safety profiles of Epiduo Gel in the treatment of facial acne in this specific younger age group are consistent with results of other pivotal studies in subjects with acne vulgaris aged 12 years and older showing significant efficacy with an acceptable tolerability. A sustained early treatment effect of Epiduo Gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-inflammatory, and Total) at Week 1 continuing to Week 12. (See Table 3.)

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Pharmacokinetics: The pharmacokinetic (PK) properties of EPIDUO are similar to the PK profile of Adapalene 0.1 % gel alone.
In a 30-day clinical PK study, conducted in patients with acne who were tested with either the fixed-combination gel or with an adapalene 0.1% matches formula under maximized conditions (with application of 2g gel per day), adapalene was not quantifiable in the majority of plasma samples (limit of quantification 0.1 ng/mL). Low levels of adapalene (C_max between 0.1 and 0.2 ng/mL) were measured in two blood samples taken from the subjects treated with EPIDUO and in three samples from the subjects treated with Adapalene 0.1 % Gel. The highest adapalene AUC _0-24h determined in the fixed-combination group was 1.99 ng·h/mL.
These results are comparable to those obtained in previous clinical PK studies on various Adapalene 0.1 % formulations, where systemic exposure to adapalene was consistently low.
The percutaneous penetration of benzoyl peroxide is low; when applied on the skin, it is completely converted into benzoic acid which is rapidly eliminated.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, phototoxicity or carcinogenicity.
Reproductive toxicology studies with adapalene have been performed by the oral and dermal routes of administration in the rat and rabbit. A teratogenic effect has been demonstrated at high systemic exposures (oral doses from 25 mg/kg/day). At lower exposures (dermal dose of 6mg/kg/day), changes in the numbers of ribs or vertebrae were seen.
Animal studies performed with EPIDUO include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and minipig up to 13 weeks and demonstrated local irritation and a potential for sensitisation, as expected for a combination containing benzoyl peroxide. Systemic exposure to adapalene following repeat dermal application of the fixed combination in animals is very low, consistent with clinical pharmacokinetic data. Benzoyl peroxide is rapidly and completely converted to benzoic acid in the skin and after absorption is eliminated in the urine,
with limited systemic exposure.