Adapalene

Abstract

Adapalene, a naphthoic acid derivative with retinoid-like activity, is used for the topical treatment of mild to moderate acne vulgaris. It binds to retinoic acid receptors found predominantly in the terminal differentiation zone of epidermis and is more active than tretinoin in modulating cellular differentiation. Adapalene exhibits anti-inflammatory activity in various in vitro and in vivo models. To date, adapalene 0.1% gel and lotion formulations have been compared only with tretinoin 0.025% gel. In these comparisons, adapalene 0.1% aqueous gel was at least as effective as tretinoin and in some studies was significantly better at reducing the numbers of noninflammatory, inflammatory and total facial lesions in patients with mild to moderate acne. In such comparisons, the cutaneous tolerability of adapalene aqueous gel was generally better than that of tretinoin. On the basis of published data, adapalene aqueous 0.1% gel is an effective and generally better tolerated alternative to tretinoin 0.025% gel for the topical treatment of patients with mild to moderate acne. Acne vulgaris is a multifactorial disease affecting the pilosebaceous units of the skin. Blockage of these units may lead to the development of acne lesions. Abnormal desquamation, defective keratinisation, blockage of the follicular orifice and consequent impaction of sebum all encourage proliferation of Propionibacterium acnes. Accumulation of sebum and keratinous debris results in a visible comedo, or whitehead, and its continued distension causes an open comedo or blackhead, produced by oxidation of keratinous material and lipids. Some comedones evolve into inflammatory papules, pustules, nodules or granulomatous lesions. The ultimate severity of the disease may depend on the degree of hypersensitivity of a patient to P. acnes and its metabolic products. The biological effect of tretinoin is mediated by cytosolic binding proteins and retinoic acid receptors (RARs). Adapalene shows the greatest affinity for the subtype RARγ, found predominantly in the epidermis. The activity of adapalene in inhibiting cell proliferation is similar to that of tretinoin, but adapalene was ≥3-fold more active than tretinoin in modulating cell differentiation in vitro. In the rhino mouse, a mutant strain of hairless mouse with horn-filled utriculi reminiscent of human microcomedones, adapalene produced a dose-related reduction in the number of epidermal comedones and an increase in comedo profile and epidermal thickness. These effects of adapalene 0.1% were similar to those observed with tretinoin 0.025%. In vitro, adapalene was more active than indomethacin, betamethasone valerate, tretinoin, isotretinoin or etretinate in inhibiting lipoxygenase activity, but it had little activity against cyclo-oxygenase. Adapalene was active in animal models of anti-inflammatory activity, but at concentrations much higher than those used clinically. The release of adapalene, assessed by diffusion through a silastic membrane, was greater from lotion and hydroalcoholic gel formulations than from aqueous gel and cream formulations. 24 hours after topical application of radiolabelled adapalene to the skin of hairless rats, peak levels of radioactivity represented 6, 0.8 and 1.4% of the dose in stratum corneum, epidermis and dermis, respectively. Adapalene could not be detected in the plasma of patients treated topically with 0.1% gel once daily for 12 weeks. The majority of a small number of predominantly single-blind clinical studies found that adapalene 0.1% gel or lotion was similarly effective to or more effective than tretinoin 0.025% gel in reducing the numbers of noninflammatory, inflammatory and total lesions on the face of patients with mild to moderate acne. In 2 studies, adapalene gel was significantly more effective than tretinoin gel in reducing the total number of lesions. Adapalene 0.03% gel was less effective than either adapalene 0.1% gel or tretinoin 0.025% gel in reducing numbers of facial lesions. An excellent response (≥75% improvement) was achieved more often in patients treated with adapalene than in those treated with tretinoin in some studies. In one study, 29% of adapalene vs 18% of tretinoin recipients achieved an excellent response for total lesions and 31 vs 18% achieved an excellent response for noninflammatory lesions. The rate of improvement was similar with both adapalene and tretinoin. Adapalene causes generally mild skin irritation in some patients with acne treated once daily with lotion, or aqueous or alcoholic gel formulations. Adverse events such as erythema, cutaneous dryness, sensations of stinging and burning and pruritus can be expected in 10 to 40% of patients. Cutaneous tolerability was generally better with adapalene aqueous gel than with tretinoin gel. Adapalene gel 0.1% should be applied to affected areas once daily at bedtime after washing. As patients may experience increased susceptibility to sunburn, they should be advised to limit their exposure to sunlight. Although adapalene was not detected in the plasma of patients treated topically with the drug, it is rated ‘pregnancy category C’ in the US; women of child-bearing age should use an effective means of contraception when receiving the drug.