Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-acne preparations for topical use, D10AD Retinoids for topical use in acne; 
ATC code: D10AD53

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 Cutibacterium 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 C. acnes strains. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.
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 20 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:
(1) Success rate, percentage of patients rated 'Clear' and 'Almost Clear' at Week 12 based on the Investigator's Global Assessment (IGA);
(2) Change and Percent Change from baseline at Week 12 in:
•     Inflammatory 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.
Table 1 Clinical efficacy in two comparative trials


Study 1
Study 1                                         Adapalene+BPO            Adapalene             BPO              Vehicle Week 12 LOCF; ITT                                    N=149                 N=148              N=149              N=71 
Success (Clear, Almost Clear)                      41 (27.5%)            23 (15.5%)         23 (15.4%)          7 (9.9%) p=0.008            p=0.003           p=0.002

Median Reduction (% Reduction) in

Inflammatory Lesion Count                          17 (62.8 %)           13 (45.7 %)        13 (43.6 %)       11 (37.8 %) p<0.001            p<0.001           p<0.001
17 (33.3 %)        16 (36.4 %)       14 (37.5 %)
Non-inflammatory Lesion Count                      22 (51.2 %)            p<0.001            p<0.001           p<0.001 Total lesion Count                                 40 (51.0 %)           29 (35.4 %)        27 (35.6 %)       26 (31.0 %) p<0.001            p<0.001           p<0.001

Study 2
Study 2                                         Adapalene+BPO            Adapalene             BPO              Vehicle Week 12 LOCF; ITT                                    N=415                 N=420              N=415              N=418 
Success (Clear, Almost Clear)                     125 (30.1%)            83 (19.8%)         92 (22.2%)        47 (11.3%) p<0.001            p=0.006           p<0.001

Median Reduction (% Reduction) in
14 (50.0 %)        16 (55.6 %)       10 (34.3 %)
Inflammatory Lesion Count                          16 (62.1 %) p<0.001            p=0.068           p<0.001
Non-inflammatory Lesion Count                      24 (53.8 %)           22 (49.1 %)        20 (44.1 %)       14 (29.5 %) p=0.048            p<0.001           p<0.001

Total Lesion Count                                 45 (56.3 %)           39 (46.9 %)        38 (48.1 %)       24 (28.0 %) p=0.002            p<0.001           p<0.001


Table 2 Clinical efficacy in combined comparative trials



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 and continuing to Week 12.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
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% matched formula under maximised conditions (with application of 2 gram gel per day), adapalene was not quantifiable in the majority of plasma samples (limit of quantification 0.1 ng/ml). Low levels of adapalene (Cmax 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.