Evaluation of Topical Dutasteride as a Potential New Therapy for Facial Acne Vulgaris Versus the Triple Combination Therapy (Clindamycin Phosphate 1.2%, Benzoyl Peroxide 3.1%, and Adapalene 0.15% Gel)

Overview

Acne vulgaris (AV) is one of the most prevalent dermatological conditions worldwide, affecting approximately 85% of adolescents and young adults between the ages of 12 and 24 years .While acne is often self-limiting, it can have profound psychosocial implications as individuals with acne are more likely to experience emotional distress, lower self-esteem and anxiety disorders . Acne Vulgaris is a chronic inflammatory skin condition affecting the pilosebaceous units that leads to the development of different skin lesions such as comedones, papules, pustules, nodules and cystic lesions .

The pathogenesis of AV involves the interaction of several host factors, including the stimulation of sebaceous glands by circulating androgens, follicular occlusion, dysbiosis of the pilosebaceous unit, and cellular immune/inflammatory responses . Despite the availability of a wide range of treatment modalities, acne management remains challenging due to factors such as antibiotic resistance, patient adherence issues, and the varying response to treatments based on individual skin types . However, recent advances in understanding the pathogenesis of acne and developing novel therapeutic modalities have reshaped the landscape of its management . Topical treatments remain the cornerstone of initial acne therapy and are favored over systemic options due to their lower risk of adverse effects and suitability for prolonged use. However, increasing concerns over antibiotic resistance and suboptimal outcomes have led to the exploration of alternative topical therapies . The American Academy of Dermatology guidelines recommend a multimodal approach to therapy incorporating agents with multiple mechanisms of action to address the multifactorial pathogenesis of acne .Thus, combining treatments in an easy-to-use, fixed-dose formulation can improve treatment adherence by reducing complex drug regimens hence improve efficacy . Adapalene is a third-generation retinoid that modulates cellular keratinization, differentiation, and proliferation . Furthermore, it is one of the most tolerable retinoids that retains its stability in the presence of Benzoyl peroxide (BPO). Benzoyl peroxide is an antibacterial agent with mild comedolytic activity, keratolytic effects, and good efficacy and tolerability . It is unaffected by Cutibacterium acnes (C. acnes) resistance and has been used in combination with topical and oral antibiotics because of its ability to reduce resistant C. acnes populations . Moreover, topical and oral antibiotics reduce C. acnes colonization and proliferation . Clindamycin is a widely researched and commonly prescribed antibiotic with anti-inflammatory effects that has been used for acne treatment for over 30 years . Adding clindamycin to BPO not only increases antibiotic activity , but also lessens irritation . Altogether, the combination of these three acne treatments targets three of the four acne pathogenic pathways and may reduce the antibiotic resistance and adverse cutaneous effects observed with .Thus, CabtreoTM (1.2% clindamycin phosphate, 0.15% adapalene, and 3.1% benzoyl peroxide) topical gel was approved by the US Food and Drug Administration (FDA) in October 2023 for the treatment of moderate to severe acne vulgaris in patients aged ≥12 years . The pathophysiology of acne is profoundly influenced by hormonal factors, particularly those that alter sebaceous gland function. Androgen hormones play a key role in acne development, with acne prevalence reaching up to 96.0% during adolescence because of changes in androgen levels during puberty . They drive acne development by altering the pilosebaceous unit, resulting in increased sebum production, keratinocyte proliferation, and inflammation . Sebum secretion by the sebaceous glands is accelerated by the conversion of testosterone to 5α dihydrotestosterone (DHT) by type I 5α-reductase (5AR), which is strongly expressed in the sebaceous glands. Therefore, it has been proposed that type I 5AR inhibitors have the potential to improve AV . Dutasteride inhibits both type I and type II 5α-reductase enzymes. It is approximately 100 times and 3 times more potent than finasteride to inhibit the type I and II 5α-reductase isoenzymes, respectively. Moreover, Dutasteride can also decrease serum DHT by \>90%, being more effective than finasteride at reducing DHT levels . Oral dutasteride is FDA approved for benign prostatic hyperplasia in men and is used off-label for androgenetic alopecia in both men and women .The oral formulation of dutasteride is associated with fewer side effects than finasteride but there is still elevated incidence of side effects such as sexual dysfunction ,decreased libido ,erectile dysfunction and depression .However, the topical formulation would have negligible systemic absorption, resulting in minimal systemic side effects and better drug availability at the site of action thereby offering better efficacy without any safety concerns . Dutasteride topical solution has been previously used for treating male baldness with different concentrations. The 0.05% concentration demonstrated better efficacy than finasteride (1 mg/day). Moreover, topical dutasteride was well-tolerated, with minimal dermal irritation and no significant adverse events or withdrawals, thereby confirming its favorable safety profile. The skin microbiome plays a role in maintaining skin health by balancing homeostatic relationships. Recent studies of AV have highlighted the role of the skin microbiome, shifting focus from individual pathogens to microbial community dynamics . While the proliferation of C. acnes has been associated with acne, it is the diversity and specific phylotypes of C. acnes that are more directly implicated in acne development . Different strains of C. acnes can induce varying immune responses. Acne-associated strains trigger pro-inflammatory cytokines like interferon (IFN)-γ and interleukin (IL)-17, whereas health-associated strains promote the production of the anti-inflammatory IL-10 . Cutibacterium acnes plays a pivotal role in acne pathogenesis by interacting with innate immunity through the release of extracellular enzymes and reactive oxygen species and the activation of Toll like receptors, alongside influencing sebum production, keratin, filaggrin, and insulin growth factor-1 levels. This leads to inflammation and hyperkeratosis, which maintains inflammation through acquired cell-mediated responses via T- helper 1 cells . Bacterial biofilms are heterogeneous structures consisting of aggregates of bacterial populations embedded in a matrix that constitutes a reservoir of bacteria. The pathogenic role of biofilms is now well established in the development and exacerbation of chronic inflammatory skin diseases such as acne. The intricate composition of the biofilm protects bacteria from antibiotics and the immune system's activity. Thus, it is challenging to eradicate a bacterial biofilm once set . Current research about acne treatment explores various facets, including sebaceous gland activity, inflammation, microbial flora and biofilm, and even systemic influences like diet, unveiling promising candidates, each targeting different aspects of acne's multifactorial nature .