Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-acne preparations for topical use, ATC code: D10AD53 
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 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 Forte 0.3%/2.5% gel applied once daily for the treatment of acne vulgaris were assessed in a 12-week, multicenter, randomized, 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 2 for the combined moderate and severe acne populations.
Table 2: Clinical efficacy in the overall population: patients with moderate and severe acne vulgaris at Week 12 (combined IGA = 3 and 4, MI, ITT population)
Adapalene            Vehicle Gel
Epiduo Forte 0.3%/2.5% 0.1%/benzoyl peroxide
Efficacy Parameters                                  Gel                  2.5% Gel              (N=69) (N=217)                  (N=217) a

Success rate
(minimum 2-grade improvement and IGA        33.7%b                    27.3%                     11.0% "clear" or "almost clear")


Change in Inflammatory
27.8b                     26.5                      13.2
Lesions,
(68.7%)                   (69.3%)                   (39.2 %)
Mean absolute (percent) reduction
Change in Non-inflammatory                  40.5b
Lesions,                                                              40.0                      19.7 (68.3 %)
Mean absolute (percent)                                               (68.0 %)                  (37.4 %) reduction

MI= Multiple Imputation; ITT= Intent-to-treat a) This study was not designed or powered to compare formally the efficacy of Epiduo Forte 0.3%/2.5% to the lower strength Adapalene 0.1% / Benzoyl peroxide 2.5% , nor to compare the lower strength Adapalene 0.1% / Benzoyl peroxide 2.5% to the Vehicle gel
 b)   p<0.001 vs Vehicle

Results of primary efficacy analyses in the severe acne population are shown in Table 3.
Table 3: Clinical efficacy in patients with severe acne vulgaris (IGA = 4, MI, ITT population) 
Adapalene 0.1%/                    Vehicle Gel
Epiduo Forte 0.3%/2.5% benzoyl peroxide 2.5%
Efficacy Parameters                                   Gel           Gel                                  (N=34) (N=106)        (N=112)

Success Rate
(minimum 2-grade improvement and IGA        31.9%a                    20.5%                     11.8% "clear" or "almost clear")


Change in Inflammatory
37.3b
Lesions,                                                              30.2                      14.3 (74.4%)
Mean absolute (percent)                                               (68%)                     (33.0%) reduction

Change in Non-inflammatory                  46.3b
Lesions,                                                              43.9                      17.8 (72.1%)
Mean absolute (percent)                                               (68.4 %)                  (30.8 %) reduction

MI= Multiple Imputation; ITT= Intent-to-treat a) p=0.029 vs Vehicle b) p<0.001 vs Vehicle

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%).


The effect of Epiduo Forte 0.3%/2.5% gel on acne scarring was investigated in the OSCAR study. This was a multi- center, randomized, investigator-blinded, vehicle-controlled trial using intra-individual comparison (right half-face vs.
left half-face) investigating male and female subjects aged 16 to 35 years (n=67) with moderate to severe facial acne vulgaris, with an average mean number of acne lesions of 40 acne lesions (18 inflammatory lesions, 22 non- inflammatory lesions) on each side. The vast majority of subjects had a global moderate severity of acne (93%). Both sides were well-balanced regarding the acne lesions, the severity of acne scars were 12 scars on each side with a majority of 2-4 mm scars.
Majority of subjects had a globally mild (63%) severity of scars and about 30% had moderate severity.

Male or female subjects aged 16 to 35 years inclusive and with skin phototype of I to IV on Fitzpatrick's scale were included in this study.

The enrolled population were mainly females (65.7%), and most subjects were categorized as mostly white by race (86.6%) and rest Asians (13.4%), ethnicity was not captured. The most frequent skin phototypes were II (47.8%) and III (34.3%) and rest IV (13.4%) and I (4.5%).

All eligible subjects were randomized to receive Epiduo Forte 0.3%/2.5% on one half of the face and vehicle gel on the other, once daily at night, for 24 weeks. The primary efficacy endpoint was atrophic acne scar count per half-face at Week 24.

The primary endpoint analysis showed that drug therapy reduced the total number of acne scars (see Table 4).

Table 4: Total acne scars (ITT/LOCF)
Epiduo Forte            Vehicle gel      Treatment               Statistical Total acne scars (ITT/LOCF)          0.3%/2.5% gel                            difference              result 

Mean ±SD                             9.5 ± 5.5               13.3 ± 7.4       -3.7 ± 4.4 
Median                               8.0                     13.0             -3.0 p<0.0001
(Q1, Q3)                             (6.0, 12.0)             (8.0, 19.0)      (-7.0, 0.0) 
(Min, Max)                           (0, 27)                 (0, 36)          (-16, 3) 
Epiduo Forte 0.3%/2.5% gel primarily reduced scars of 2-4 mm size (mean Epiduo Forte 0.3%/2.5% gel 9.0 ± 5.4; mean Vehicle gel 12.1 ± 7.0; mean treatment difference vs. vehicle -3.1 ± 4.1), while the reduction in scars of >4 mm was smaller (mean Epiduo Forte 0.3%/2.5% gel 0.6 ± 0.8; mean Vehicle gel 1.2 ± 1.9; mean treatment difference vs.
vehicle -0.6 ± 1.5).

Figure 1 shows the percent change of total atrophic scars by visit for the Epiduo Forte 0.3%/2.5% gel and vehicle face halves, respectively.

Figure 1



* nominal p-value, not adjusted for multiple testing

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
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 Cmax of 0.16 ± 0.08 ng/mL and a mean AUC0-24h of 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene Cmax and AUC0-24h 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 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.