Epiduo Forte Mechanism of Action

Pharmacotherapeutic group: Anti-Acne Preparations for Topical Use. ATC code: D10AD53.
Pharmacology: Pharmacodynamics: Mechanism of action and Pharmacodynamic effects: Epiduo Forte 0.3% / 2.5% gel 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 Propionibacterium acnes, which is abnormally present in the acne-affected pilosebaceous unit. The mechanism of action of Benzoyl peroxide has been explained by its highly lipophilic activity, enabling its penetration through the epidermis into bacterial and keratinocyte cell membranes of the pilosebaceous unit. Benzoyl peroxide is recognized as a very effective broad-spectrum antibacterial agent in the treatment of acne vulgaris. It has been demonstrated to exert bactericidal effect by generating free radicals that oxidize proteins and other essential cellular components in the bacterium wall. The minimum inhibitory concentration of benzoyl peroxide is bactericidal and has demonstrated effectiveness on antibiotic-sensitive and antibiotic-resistant P. acnes strains. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
Clinical efficacy and safety: The safety and efficacy of Epiduo Forte 0.3% / 2.5% gel applied once daily for the treatment of acne vulgaris were assessed in a 12-week, multicenter, randomised, double-blind, controlled clinical study, comparing Epiduo Forte 0.3% / 2.5% gel to the gel vehicle in 503 acne patients. In this study, 217 patients were treated with Epiduo Forte 0.3% / 2.5% gel, 217 patients with adapalene 0.1% / benzoyl peroxide 2.5% gel and 69 patients with the Vehicle gel.
The efficacy criteria were: Success rate, defined as the percent of subjects who were rated 'Clear' or 'Almost Clear' at Week 12 with at least a two-grade improvement based on the Investigator's Global Assessment (IGA). An IGA score of 'Clear' corresponded to clear skin with no inflammatory or non-inflammatory lesions. An IGA score of 'Almost Clear' corresponded to a few scattered comedones and a few small papules.
Mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts.
At Baseline, 50% of enrolled patients had acne severity assessed as "moderate" (IGA=3) and 50% had scores of "severe" (IGA=4). In the overall study population, up to two nodules were allowed. For lesion counts, subjects had an average of 98 total lesions (range: 51-226), of which the mean number of inflammatory lesions was 38 (range: 20-99) and the mean number of non-inflammatory lesions was 60 (range: 30-149). The age of the patients ranged from 12 to 57 years (mean age: 19.6 years), with 273 (54.3%) patients 12 to 17 years of age. A similar number of males (47.7%) and females (52.3%) were enrolled.
In this pivotal study, 55.2% of patients in the severe stratum had truncal acne. The patients treated the face and other acne affected areas on the trunk as needed once daily in the evening.
Statistical analyses were performed to compare and interpret study results in a stepwise manner: Epiduo Forte 0.3% / 2.5% gel versus Vehicle gel in the overall population of patients with moderate and severe acne (IGA=3 and IGA=4); Epiduo Forte 0.3% / 2.5% gel versus Vehicle gel in the subgroup of patients with severe acne (IGA=4).
The efficacy results are shown in Table 1 for the combined moderate and severe acne populations. (See Table 1.)

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Results of primary efficacy analyses in the severe acne population are shown in Table 2. (See Table 2.)

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Adapalene 0.1% / benzoyl peroxide 2.5% gel was included in this trial as a reference therapy. In subjects graded as "moderate" (IGA Grade 3), Epiduo Forte 0.3% / 2.5% gel showed no efficacy advantage compared with the reference therapy. In the analysis in subjects graded as "severe" (IGA Grade 4), Epiduo Forte 0.3% / 2.5% gel achieved a greater efficacy over vehicle with a treatment difference of 20.1% (31.9% vs. 11.8%; 95% CI: [6.0%, 34.2%)], p=0.029), whereas the reference therapy did not (treatment difference vs. vehicle of 8.8%).
Pharmacokinetics: Absorption: A pharmacokinetic study was conducted with Epiduo Forte 0.3% / 2.5% gel in 26 adult and adolescent subjects (12 to 33 years of age) with severe acne vulgaris. The subjects were treated with once daily applications on all potentially affected areas during a 4 week period with, on average, 2.3 grams/day (range: 1.6-3.1 grams/day) of Epiduo Forte 0.3% / 2.5% gel applied as a thin layer to the face, shoulders, upper chest and upper back. After 4 weeks of treatment, 16 subjects (62%) had quantifiable adapalene plasma concentrations above the limit of quantification (LOQ of 0.1 ng/mL), with a mean C_max of 0.16 ± 0.08 ng/mL and a mean AUC_0-24h of 2.49 ± 1.21 ng·h/mL. The most exposed subject had adapalene C_max and AUC_0-24h values of 0.35 ng/mL and 6.41 ng·h/mL, respectively.
Pharmacokinetics studies conducted with both Epiduo and Epiduo Forte 0.3% / 2.5% Gels have evidenced that the transdermal absorption of adapalene is not affected by benzoyl peroxide.
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 6 mg/kg/day), changes in the numbers of ribs or vertebrae were seen.
Animal studies performed with Epiduo or with Epiduo Forte 0.3% / 2.5% gel include local tolerance studies and dermal repeat-dose toxicity studies in rat, dog and/or 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.