Mechanism of Action

Azelaic acid exerts its keratolytic and comedolytic effects by reducing the thickness of the stratum corneum and decreasing the number of keratohyalin granules by reducing the amount and distribution of filaggrin in epidermal layers. Azelaic acid also possesses a direct anti-inflammatory effect due to its scavenger activity of free oxygen radical. It is used topically to reduce inflammation associated with acne and rosacea.

Pharmacodynamic Properties

Acne

An antimicrobial action and a direct influence on follicular hyperkeratosis are assumed to be the basis for the therapeutic efficacy of azelaic acid in acne.

In vitro and in vivo, azelaic acid inhibits the proliferation of keratinocytes and normalizes the disturbed terminal epidermal differentiation processes in acne.

Clinically, a significant reduction of the colonization density of Propionibacterium acnes and a significant reduction in the fraction of free fatty acids in the skin surface lipids are observed.

In vitro and in vivo, azelaic acid inhibits the proliferation of keratinocytes and normalizes the disturbed terminal epidermal differentiation processes in acne. In the rabbit ear model, azelaic acid accelerates the comedolysis of tetradecane-induced comedones.

In two double blind randomized clinical studies azelaic acid gel was significantly superior to its vehicle in the median reduction of the sum of papules and pustules, and was 6% less effective than benzoyl peroxide 5% (p=0.056).

In these studies effectiveness of azelaic acid gel on comedones has been evaluated as a secondary parameter. Azelaic acid gel was more effective than its vehicle in the median relative reduction of comedones, and was less effective in comparison to benzoyl peroxide 5%.

Rosacea

While the pathophysiology of rosacea is not completely understood, there is increasing consensus that inflammation involving the elevation of several pro- inflammatory effector molecules such as kallikrein-5 and cathelicidin as well as reactive oxygen species (ROS), is a central process of this disease.

Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes by: a) activating the peroxisome proliferator-activated receptor ╬│ (PPAR╬│); b) inhibiting the trans-activation of nuclear factor-kB (NF-kB); c) inhibiting the production of pro-inflammatory cytokines and d) inhibiting the release of ROS from neutrophils, as well as direct scavenging effects on existing ROS.

In addition, azelaic acid has been shown to directly inhibit kallikrein-5 and cathelicidin expression in three models: in vitro (human keratinocytes), in murine skin and in the facial skin of patients with rosacea.

These anti-inflammatory properties of azelaic acid may play a role in the treatment of rosacea.

While the clinical significance of these findings regarding kallikrein-5 and cathelicidin and their impact on the pathophysiology of rosacea has not yet been fully demonstrated in a large clinical study, initial studies in human facial skin appear to confirm the in vitro and murine findings.

In the two vehicle controlled 12 week clinical studies in papulopustular rosacea, azelaic acid gel was statistically significantly superior to its vehicle with regard to the reduction in inflammatory lesions, Investigator’s Global Assessment, overall rating of improvement and with regard to improvement of erythema.

In the clinical study with the active comparator metronidazole 0.75% gel in papulopustular rosacea, azelaic acid gel showed significant superiority with regard to lesion count reduction (72.7% versus 55.8%), overall rating of improvement and with regard to improvement of erythema (56% versus 42%). The rate of cutaneous adverse events, which in most cases were mild to moderate, was 25.8% with azelaic acid gel and 7.1% with metronidazole 0.75% gel.

There was no noticeable effect on the teleangiectasias in the three clinical studies.

Pharmacokinetic Properties

After dermal administration of the cream, azelaic acid penetrates into all layers of human skin. The penetration is more rapid into damaged skin than into intact skin. A total of 3.6% of the administered dose was absorbed percutaneously after a single topical administration of 1 g azelaic acid (5 g cream).

A portion of the azelaic acid which is absorbed through the skin is eliminated unchanged with the urine. The remaining portion is metabolized through beta- oxidation into short-chained dicarboxylic acids (C7, C5 carboxylic acids) which have likewise been found in the urine.

Steady-state plasma levels of azelaic acid in rosacea patients after 8 weeks twice daily treatment with azelaic acid gel were within the range also observed in volunteers and acne patients on normal diets. This indicates that the extent of percutaneous absorption of azelaic acid following twice daily application of azelaic acid gel does not alter the systemic burden of azelaic acid derived from dietary and endogenous sources in a clinically meaningful way.

Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, contact hypersensitivity, genotoxicity and toxicity to reproduction and development.

Embryofetal developmental studies with oral administration of azelaic acid to rats, rabbits, and cynomolgus monkeys during the period of organogenesis revealed embryotoxicity at doses where some maternal toxicity was noted. No teratogenic effects were observed. The embryofetal NOAEL was 32 times the MRHD based on BSA in rats, 6.5 times the MRHD based on BSA in rabbits and 19 times the MRHD based on BSA in monkeys.

In a peri- and post- natal developmental study in rats where azelaic acid was administered orally from gestational day 15 to through day 21 postpartum slight disturbances in the post-natal development of fetuses were noted at oral doses that generated some maternal toxicity. The NOAEL was 3 times the MRHD based on BSA. No effects on sexual maturation of the fetuses were noted in this study.

In vitro and in vivo studies with azelaic acid produced no evidence of mutagenic effects on germ and somatic cells. Conventional long-term carcinogenicity studies with oral administration of azelaic acid have not been performed. In a 26-week dermal carcinogenicity study using male and female transgenic (Tg.AC) mice, azelaic acid gel and the gel vehicle did increase the number of papillomas in male animals after twice daily application at the treatment site. This effect was not observed after single administration in male and female mice. This effect may be associated with the vehicle application. The clinical relevance of the findings in animals to humans is not clear, especially in the light of the doubtful validity of the Tg.AC test system.

Studies on impairment of fertility in animals have not produced any evidence for such a risk during therapeutic use of azelaic acid.

If azelaic acid came into contact with the eyes of monkeys and rabbits, signs of moderate to severe irritation became evident. Therefore, contact with the eyes should be avoided.

Azelaic acid administered once intravenously had no effects on the nervous system (Irwin test), cardiovascular function, intermediary metabolism, smooth muscles and liver and kidney function.

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