Azelaic Acid

Summary

Synopsis

Azelaic acid is a naturally occurring saturated dicarboxylic acid which, on topical application (usually as a 20% cream), has been shown to be effective in the treatment of comedonal acne and inflammatory (papulopustular, nodular and nodulocystic) acne, as well as various cutaneous hyperpigmentary disorders characterised by hyperactive/abnormal melanocyte function, including melasma and, possibly, lentigo maligna. In addition, azelaic acid has an antiproliferative and cytotoxic effect on the human malignant melanocyte, and preliminary findings indicate that it may arrest the progression of cutaneous malignant melanoma. The mechanism of this selective cytotoxic action of azelaic acid is unclear, but may possibly be related to its inhibition of mitochondrial oxidoreductase activity and DNA synthesis. In controlled studies, topical azelaic acid demonstrated comparable antiacne efficacy to topical tretinoin, benzoyl peroxide, erythromycin and oral tetracycline, while in patients with melasma azelaic acid proved at least as effective as topical hydroquinone. On topical application azelaic acid is well tolerated, with adverse effects apparently limited to a generally mild and transient local cutaneous irritation. Thus, topical azelaic acid, employed either as monotherapy or in combination with other treatments, is likely to prove of value in the management of acne and several hyperpigmentary disorders, most notably melasma.

Pharmacodynamic Studies

Azelaic acid displays bacteriostatic and bactericidal properties against a variety of aerobic and anaerobic microorganisms present on acne-bearing skin. Topical application of 20% azelaic acid cream caused marked reductions in the densities of cutaneous micrococcaceae and intrafollicular Propionibacterium sp., and decreased the free fatty acid content of skin surface lipids. Sebum production, sebum composition and sebaceous gland morphology were not significantly altered.

In vitro, azelaic acid 20 to 50 mmol/L displayed a time- and concentration-dependent antiproliferative effect on normal human and neonatal mouse keratinocytes, mouse melanoma cells and human cutaneous and choroidal melanoma cells; a cytotoxic effect was manifest at concentrations greater than 40 mmol/L. A similar antiproliferative/cytotoxic effect has been demonstrated with human lymphoma- and leukaemia-derived cell lines and squamous carcinoma cells.

Topical 20% azelaic acid cream showed an antikeratinising effect on normal and acne-affected skin which was related to decreased synthesis of filaggrin (keratin filament aggregating protein); hence a reduction in follicular hyperkeratosis may partly underlie the drug’s anti-acne action. Azelaic acid appears to act selectively on hyperactive and abnormal melanocytes. On prolonged (≤ 3 months) topical application, 15 or 20% azelaic acid cream caused no appreciable depigmentation of normally pigmented human skin, freckles, senile lentigines or naevi, but reduced epidermal melanogenesis in patients with lentigo maligna. Combined topical and oral (10 to 15 g/day) azelaic acid therapy in patients with cutaneous malignant melanoma resulted in the degeneration and disappearance of malignant epidermal melanocytes.

The antiproliferative/cytotoxic effects of azelaic acid appear to be mediated primarily via disruption of mitochondrial respiration and/or cellular DNA synthesis, rather than via inhibition of tyrosinase activity. Ultrastructural studies demonstrated selective and marked mitochondrial swelling and vacuolation, and accumulation of cytoplasmic lipid droplets, both in cutaneous/ choroidal melanoma cells exposed to azelaic acid (≤ 100 mmol/L) in vitro and in skin biopsies obtained from patients with lentigo maligna or cutaneous melanoma treated with topical azelaic acid. Differences in cellular permeability and/or metabolic activity may account for the greater susceptibility of hyperactive and abnormal epidermal cells (keratinocytes and melanocytes) to the antiproliferative and depigmenting actions of azelaic acid.

Pharmacokinetic Studies

Azelaic acid has been administered to humans orally, by intravenous, intra-arterial and intralymphatic infusion ( 15% solution of the disodium salt) and topically (usually as 20% azelaic acid cream). In healthy volunteers, plasma azelaic acid concentrations peaked at 6 to 75 mg/L 2 hours after a single oral dose of 0.5 to 5g. Plateau plasma azelaic acid concentrations in excess of 940 mg/L (consistent with those showing antiproliferative effects in vitro) have been achieved with continuous intravenous/intra-arterial infusion. Percutaneous absorption of azelaic acid is governed by the formulation employed, varying from 3% (ointment or emulsion base) to 8% (gel) of the administered dose. In humans, azelaic acid is partially metabolised by mitochondrial β-oxidation to acetyl CoA and malonyl CoA; unchanged drug is excreted exclusively in the urine.

Therapeutic Efficacy

Under controlled conditions, twice daily topical application of 20% azelaic acid cream was markedly more effective than that of its vehicle in reducing numbers of comedones, papules and pustules in patients with mild-to-moderate acne. On completion of 3 months’ therapy, a significantly higher proportion of patients with papulopustular acne had achieved a good-to-excellent clinical response with azelaic acid (64%) than with vehicle (36%). Over 5- or 6-month treatment periods, topical 20% azelaic acid cream, applied twice daily, was of comparable efficacy to topical 0.05% tretinoin cream, topical 5% benzoyl peroxide gel, topical 2% erythromycin cream, and oral tetracycline 0.5 to 1.0 g/day in comedonal and mild-to-moderately severe inflammatory acne, producing a good-to-excellent clinical response in 65 to 80% of patients with mild-to-moderate acne and in approximately 60% of those with moderate-to-severe acne. However, topical 20% azelaic acid, administered twice daily over a 6-month period, was significantly less effective than oral isotretinoin 0.5 to 1.0 mg/kg/day in conglobate acne. Differences in the time course of the responses to azelaic acid and the various anti-acne agents included a slightly more rapid initial improvement in papulopustular acne with benzoyl peroxide.

Preliminary findings indicate that topical 20% azelaic acid cream, administered twice daily over a 6-month treatment period, is of comparable efficacy to topical 4% hydroquinone cream, and significantly superior to 2% hydroquinone cream, in reducing pigmentation and lesion size in melasma (good-to-excellent clinical response in 73 vs 19% of patients receiving azelaic acid and 2% hydroquinone, respectively).

The clinical response to topical 15 or 20% azelaic acid cream, applied twice daily for periods of 3 to 12 months, in lentigo maligna was characterised by a progressive reduction in pigmentation, flattening of indurated lesion surfaces and apparent lesion shrinkage. Although response rates showed large interstudy variation (ranging from 13 to 100%), clinical remission, once achieved, was sustained. This inconsistency of response to azelaic acid would, nevertheless, suggest that its use should be confined to those cases of lentigo maligna in which surgery is contraindicated. Similarly, while preliminary findings indicate that combined topical (20% cream) and oral (10 to 15 g/day) azelaic acid therapy may arrest lesion progression in patients with cutaneous malignant melanoma, surgical excision must remain the accepted mode of treatment for this condition. Other possible indications for azelaic acid include treatment of physical and phototoxic hyperpigmentation.

Adverse Effects

Azelaic acid, at oral doses of up to 4000 mg/kg, has shown no evident toxicity, teratogenicity or mutagenicity in animal studies, and during oral (≤ 20 g/day) or topical (20% cream) administration to humans has demonstrated no systemic adverse effects. Local cutaneous irritation, marked by erythema, pruritus, scaling and a burning sensation, occurs in 5 to 10% of patients (an incidence comparable to that seen with its cream base), and is mild and transient, generally subsiding after 2 to 4 weeks of treatment. In terms of local cutaneous effects, topical azelaic acid is well tolerated in comparison with standard topical anti-acne agents and, in addition, is free of the specific systemic effects variously associated with oral anti-acne agents: antibiotic resistance (tetracycline), mucocutaneous effects and teratogenicity (isotretinoin), potential endocrine imbalance (cyproterone acetate). The incidences of local cutaneous irritation associated with the use of topical 20% azelaic acid and 2 to 4% hydroquinone creams appear comparable.

Dosage and Administration

The topical route of administration is the only one currently available for azelaic acid. A 20% azelaic acid cream applied twice daily is most frequently employed.