Differin - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Differin - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Acne
Class: Dermatological agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Adapalene, Carbomer 934P (Carbomer 940 or Carbomer 941), cyclomethicone, edetate disodium, glycerin, methyl gluceth 20 sesquistearate, methyl glucose sesquistearate, methylparaben, phenoxyethanol, propylparaben, squalane, trolamine, and purified water, propylene glycol, sodium hydroxide and/or hydrochloric acid, medium chain triglycerides, poloxamer 124 (poloxamer 182 ), polyoxyl-6-polyoxyl-32 palmitostearate, PPG-12 / SMDI copolymer, stearyl alcohol.

Pharmaceutical Information

Drug Substance

Proxper Name: adapalene
Chemical Name: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
Molecular Formula and Molecular Mass: C28H28O3; 412.52
Structural Formula:


Physicochemical properties: Adapalene is a white to off-white powder, which is sparingly soluble in tetrahydrofuran and practically insoluble in water and ethanol (96%).

Clinical Trials

Study Demographics and Trial Design

Table 1: Summary of patient demographics for North American Phase III active- and vehicle-controlled clinical trial in acne vulgaris
Study # Trial design Dosage , route of
administration, and
duration
Study
subjects
(n=number)
Mean age
(Range)
Years
Gender
%M/F
RD.06.SRE.18081 Double-blind,
parallel,
controlled
(active &
vehicle
0.3% adapalene gel
0.1% adapalene gel
gel vehicle
Topical
12 weeks
(653)
258
261
134
18.2
(12 - 52 )
49.5/50.5
RD.06.SPR.18113
and
RD.06.SPR.18114
Double-blind,
parallel,
controlled
(active &
vehicle)
0.1% adapalene lotion
lotion vehicle
Topical
12 weeks
1068
1073
19.3 (12 - 54)
19.0 (12 - 64)
45.4/54.6
47.6/52.4
9111-CD271C-EV Parallel,
Randomized,
Double-blind,
Controlled
(active &
vehicle)
0.1% adapalene cream
cream vehicle
Topical
12 weeks
(350)
175
175
19
(12 - 31)
59/41

Male and female subjects, 12 years of age or older, were eligible to enroll in these controlled clinical trials. 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. In study RD.06.SPR.18113 and study RD.06.SPR.18114 with adapalene lotion 0.1%, patients with 20 to 50 inflammatory lesions on the face and 30 to 100 non-inflammatory lesions on the face, with no cysts and no more than one nodule on the face were eligible for enrollment. Subjects in study RD.06.SPR.18113 and study RD.06.SPR.18114 also had an Investigator's Global Assessment score of 3 (moderate) or 4 (severe) at Baseline.

Table 2: Summary of patient demographics for European Phase III active-controlled clinical trial in acnevulgaris
Study # Trial design Dosage , route of
administration, and
duration
Study
subjects
(n=number)
Mean age
(Range)
Years
Gender
% M/F
RD.03.SRE.2673 Double-
blind,
parallel,
active-
controlled
0.3% adapalene gel 0.1%
adapalene gel
Topical
12 weeks
(418)
208
210
19.1
(12 - 39 )
40.0/60.0

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

Table 3: Results of North American Study RD.06.SRE.18081 in acne vulgaris at Week 12 (Observed)
Primary Endpoints* Adapalene Gel, 0.3%
(n=227)
Adapalene Gel, 0.1%
(n=237)
Gel Vehicle (placebo)
(n=120)
Success rate [% of subjects with "Clear" or
"Almost Clear" on Investigator's
Global Assessment (IGA)]
23.3%
[p value vs 0.1%: 0.072]
[p value vs vehicle: 0.002]
16.97% 10.0%
Median % lesion count reduction
Total -55.60
[p value vs 0.1%: 0.003]
[p value vs vehicle: <0.001]
-48.25 -36.40
Inflammatory -62.50
[p value vs 0.1%: 0.099]
[p value vs vehicle: <0.001]
-57.80 -47.25
Non-inflammatory -52.10
[p value vs 0.1%: 0.003
[p value vs vehicle: <0.001]
-43.45 -29.35
Table 4: Results of North American Studies RD.06.SPR.18113 and RD.06.SPR.18114 (combined) in acne vulgaris at Week 12 (LOCF, ITT)
Primary Endpoints Adapalene Lotion 0.1%,br>(n=1068) Lotion Vehicle
(n=1073)
p-value
Success Rate
[% of patients with a Week 12
Investigator's Global Assessment (IGA)
at least 2 grades lower than Baseline]
25.2% 16.9% p<0.001a
Mean absolute (percent) reduction from Baseline in lesion counts:
Inflammatory 13.7
(-50.5%)
10.4
(-38.6%)
p<0.001b
Non-inflammatory 21.4
(-46.4%)
14.6
(-33.0%)
p<0.001b
Total 35.2
(-48.0%)
25.0
(-35.0%)
p<0.001b

aCochran-Mantel-Haenszel test, stratified by analysis centre
bANCOVA (ranked and unranked)

Table 5: Results of European Study RD.03.SRE.2673 in acne vulgaris at Week 12 (Observed)
Primary Endpoints Adapalene Gel, 0.3%
(ITT n=208)
Adapalene Gel, 0.1%
(ITT n=210)
Median % lesion count reduction
Total -67.1%
[p value vs 0.1%: 0.134]
-61.4%
Inflammatory -65.4%
[p value vs 0.1%: 0.310]
-64.0%
Non-inflammatory -68.8%
[p value vs 0.1%: 0.145]
-60.0%
Table 6: Results of North American Study 9111-CD271C-EV inacne vulgaris at Week 12 (Observed)
Primary Endpoints Adapalene Cream, 0.1%
(n=162)
Vehicle Cream
(n=167)
Median % lesion count reduction
Total -32%
[p value vs vehicle: 0.0001]
-15%
Inflammatory -15%
[p value vs vehicle: 0.2396]
-5%
Non-inflammatory -37%
[p value vs 0.05%: 0.0001]
-15%

Detailed Pharmacology

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. 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).

Human Pharmacology

Pharmacokinetics

In vitro studies

In vitro experiments on human skin showed that skin is an effective barrier to adapalene penetration. The total amount of adapalene that penetrated into the skin accounted for 1.54% ± 0.22 of a finite applied dose of DIFFERIN Lotion, 0.1%. No detectable adapalene levels were seen in the receptor fluid. The skin penetration of adapalene from the 0.1% lotion was found in vitro to be higher than with DIFFERIN 0.1% Cream (0.64% ± 0.11) but lower than with DIFFERIN 0.1% Gel (2.75% ± 0.39).

Pharmacodynamics

A clinical study in healthy subjects showed that Adapalene Vehicle Lotion and Adapalene Lotion, 0.1% had mean calculated cumulative irritancy indices of 0.37 and 0.58, respectively. The positive control (Sodium Lauryl Sulfate) and the negative control (White Petrolatum) had mean calculated cumulative irritancy indices of 2.86 and 0.38, respectively. The mean cumulative irritancy index scores of Adapalene Vehicle Lotion, Adapalene Lotion, 0.1% and the negative control are indicative of test articles with a mild irritation profile. The mean cumulative irritancy index score of the positive control is indicative of a cumulative irritant.

An additional clinical study in healthy subjects showed that Adapalene Lotion, 0.1% had a mean calculated cumulative irritancy index of 0.31, which is indicative of a test article with a mild irritation profile. Additionally, the reactivity observed with Adapalene Lotion, 0.1% was not considered evidence of induced contact sensitization.

Toxicology

Acute and Chronic Studies

The acute oral LD50 of adapalene in Sprague-Dawley rats and in Charles River CD1 mice was found to be greater than 5000 mg/kg. The acute LD50 of adapalene 0.3% gel or solution was found to be greater than 6 mg/kg in Sprague-Dawley rats (topical) and greater than 30 mg/kg in Iffa Credo OF1 mice (oral), respectively. No pharmacotoxic effects were observed in these studies.

Systemic administration of adapalene produced a hypervitaminosis A syndrome in mice, rats and dogs. In rats, it was present after four weeks at 5 mg/kg with adapalene given orally by dietary administration. The main target organ appears to be the bone.

Slight decreases in red blood cell parameters were observed in all species where adapalene was given orally. These slight changes were also observed in some topical studies in rats and rabbits, and occurred mainly with adapalene at 0.3% solution or aqueous gel. No morphological or histopathological changes were observed in bone marrow in several oral studies in rats and topical studies in rats and rabbits for periods up to six months. It is concluded that these changes were peripheral rather than central. The dose producing these minimal changes corresponds to 17 times the MRHD of adapalene 0.3% gel based on mg/m5 comparisons for rats and 32 times the MRHD for rabbits.

Changes in clinical chemistry parameters (mostly decreases in protein and albumin concentrations, and increases in triglyceride concentration and liver-specific alkaline phosphatase activity) were observed in animals when adapalene was administered dermally (rats) or orally (rats and dogs). The effects were dose related, but reversible in recovery studies.

Given topically in solution (rabbits) or in aqueous gel (rabbits and mice), adapalene gave slight to moderate irritation according to the concentration and the duration and frequency of treatment.

Following 26 weeks of daily cutaneous application to rats at concentrations of up to 0.3% (6 mg/kg/day), adapalene gel was well tolerated. The dose related changes observed included erythema, flaking, and acanthosis at the application site, all of which were reversible over the course of an 8 week recovery period.

Adapalene lotion 0.1%, at doses up to 1.2 mg/kg/day, was applied to the skin of minipigs in a 3-month dermal toxicity study with toxicokinetic analysis. Most of the treatment-related effects were of a local dermal nature including very slight erythema with very slight or slight edema to minimal eschar formation. These mild signs of skin irritation essentially disappeared by the end of the one month recovery period. There were no signs of systemic toxicity. No significant plasma levels of drug were observed on day 1, and after 91 days of repeated application, plasma levels were noted in some of the animals in the 0.2 mg/kg/day group and in most of the animals in the 0.6 and 1.2 mg/kg/day groups, although levels were very variable. Plasma steady-state levels were probably not reached in all animals by day 91. The NOAEL for this study was considered to be the high dose of 1.2 mg/kg/day.

Carcinogenicity Studies

Lifetime studies with adapalene have been completed in mice at topical doses of 0.6 (0.03%), 2 (0.1%) and 6 (0.3%) mg/kg/day and in rats at oral doses of 0.15, 0.5 and 1.5 mg/kg/day and demonstrated no carcinogenic effect. However, a high incidence of splenic extra-medullary haematopoiesis was observed in male mice treated with 6 mg/kg/day (0.3%) topically applied adapalene gel. Oral administration of adapalene to Sprague-Dawley rats at a dose of 1.5 mg/kg/day for two years resulted in a higher incidence in males, relative to controls, of benign phaeochromocytoma of the adrenal medulla. These neoplastic changes are considered to have no relevance to the topical use of adapalene in humans in clinical conditions.

Animal studies have shown an increased tumorigenic risk with the use of related drugs (e.g., tretinoin) when combined with exposure to the ultraviolet (UV) light in sunlight, or from other UV sources. Studies to determine whether adapalene may accelerate the tumorigenic effects of UV radiation have not been conducted.

Mutagenicity Studies

In a series of in vivo and in vitro tests, adapalene did not demonstrate any mutagenic or genotoxic activity.

Reproductive and Teratology Studies

Adapalene administered orally at doses of ≥ 25 mg/kg/day can induce major structural changes including cleft palate, cranial abnormalities and spina bifida in rat and rabbit foetuses. Similar teratogenic effects have also been reported with other retinoids.

In the topical studies at the clinical concentration of 0.3% (equivalent to 6 mg/kg/day of applied adapalene, and corresponding to 17 times the MRHD for rats or 32 times the MRHD for rabbits), increases in additional foetal rib numbers were recorded in both rats and rabbits. In the rat, there were also other minimal increases in skeletal anomalies such as small additional fissure in the parietal bone and asymmetric pelvis. In the rabbit, the skeletal anomalies were small additional fissures in the inter-parietal bone, 27 pre-sacral vertebrae, incomplete ossification of the head of limb long bones, and tail anomalies.

In the topical studies at the clinical concentration of 0.1% (equivalent to 2 mg/kg/day of applied adapalene), no adverse effects were observed in rabbits and only a marginal increase in the incidence of rudimentary additional lumbar ribs in rats was observed. The doses used in the topical teratology studies correspond to about 51 and 96 times the MRHD of adapalene 0.1% in the rat and rabbit respectively.

No effects of adapalene (doses up to 20 mg/kg/day) were found in rats on the reproductive performance or fertility of the F0 males or females. Total litter loss was suffered by 3 out of 25 F0 female rats (12%) orally dosed at 15 mg/kg/day; these females had pale and inactive mammary tissues. There were no detectable effects on the growth, development and subsequent reproductive function of the F1 offspring.