Paradigm Shift in the Management of Topical Tinea Infections Dr Hardik Pathak
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Review Article Luliconazole: Paradigm Shift in the Management of Topical Tinea Infections Dr Hardik Pathak Abstract Luliconazole is an imidazole topical antifungal agent with a unique structure. Pre-clinical studies have dem- onstrated excellent activity against dermatophytes. Although luliconazole belongs to the azole group, it has strong antifungal activities against Trichophyton spp. This may be attributed to a combination of strong in vi- tro antifungal activity and favourable pharmaco kinetic properties in the skin. Clinical trials have demonstrat- ed its superiority over placebo in dermatophytosis, and performed better than terbinafine. The frequency of application (once daily) and duration of treatment (one week for tinea corporis/cruris and 2 weeks for inter- digital tinea pedis) was favourable when compared to other topical regimens in treating tinea pedis. Such regimens include 2–4 weeks of twice-daily treatment with econazole, up to 4 weeks of twice-daily treatment with sertaconazole, 1–2 weeks of twice-daily treatment with terbinafine, 4 weeks of once-daily application of naftifine and 4–6 weeks of once-daily treatment with amorolfine. Luliconazole 1% cream was approved in Japan in 2005 for the treatment of tinea infections. Recently, the US Food and Drug Administration (USFDA) approved luliconazole for interdigital tinea pedis, tinea cruris, and tinea corporis treatment. Topical lulicon- azole has a favourable safety profile, with mild application-site reactions reported occasionally. Keywords: Luliconazole, Tinea pedis, Tinea corporis, Tinea cruris, once a daily Conflict Of Interest: Dr Hardik Pathak is a salaried employee of Dr. Reddy’s Laboratories Ltd, Hyderabad, Telangana, India. Dermatophytosis: A Global Burden (1) he prevalence of superficial mycotic infection is hair, and nails), Epidermophyton (skin and nails), and 20–25% worldwide; most common agents be- Microsporum (skin and hair). Trichophyton rubrum is Ting the dermatophytes. Recent developments in the most common isolate with tinea corporis and cru- understanding the pathophysiology of dermatophy- ris; the most common clinical presentation in relatively tosis confirmed the central role of cell-mediated im- large studies from India. munity in countering these infections. Hence, a lack of (1) delayed hypersensitivity reaction in the presence of a Non-Pharmacologic Measures Patients should be encouraged to wear loose-fitting positive immediate hypersensitivity (IH) response to garments made of cotton or synthetic materials de- trichophytin antigen points towards the chronic con- signed to wick moisture away from the surface. Socks dition of the disease. should have similar properties. Areas likely to become Dermatophytes are fungi that invade and multiply infected should be dried before being covered with within keratinized tissues (skin, hair, and nails) caus- clothes. Patients should also avoid walking barefoot ing infection. Based upon their genera, dermatophytes and sharing garments. can be classified into three groups: Trichophyton (skin, Dr Hardik Pathak works with Dr. Reddy’s Laboratories Ltd, Hyderabad, Telangana, India. 42 The Indian Practitioner q Vol.72 No.2. February 2019 Review Article Table 1: Classification of anti-fungal agents tions, fungicidal activity with convenient Antifungal class Examples dosing schedules, keratinophilic and lipo- Antibiotics philic effects, high mycologic clinical cure rates, a reservoir effect in the stratum cor- Polyenes Amphotericin B, nystatin, natamycin neum, lack of development of fungal re- Heterocyclic Griseofulvin benzofuran sistance, low relapse rates, minimum side- effects, and low cost. Antimetabolite Flucytosine Azoles Luliconazole: Unique Topical Anti-Fungal Imidazoles Topical - clotrimazole, econazole, miconazole, Agent with Multiple Advantages (1-3) bifonazole, fenticonazole, oxiconazole, tioconazole, Luliconazole, also known as NND-502, sertaconazole, berconazole, luliconazole, is an imidazole antifungal first synthesized eberconazole by Nihon Nohyaku Co Ltd (Osaka, Japan). Systemic - ketoconazole Japan approved Luliconazole 1% cream Triazoles Itraconazole, fluconazole (also topical), voriconazole, in 2005 for tinea infection, followed by US posaconazole, isavuconazole, posoconazole, ravuconazole, pramiconazole, albaconazole Food and Drug Administration (USFDA) approval in November 2013 for interdigital Allylamines Terbinafine, butenafine, naftifine tinea pedis, tinea cruris, and tinea corporis Echinocandins Caspofungin, anidulafungin, micafungin, aminocandin caused by the organisms T. rubrum and E. floccosum. India approved the 1% cream in Sordarin derivatives GR135402, GM237354 2009. The 1% cream formulation is effective Cell wall antagonist Capsofungin, micafungin at the infection site when applied once daily Other agents Tolnaftate, ciclopirox, amorolfine, undecylenic acid, for 1–2 weeks. buclosamide, whitfield’s ointment, benzoyl peroxide, zinc pyrithione, selenium sulfide, azelaic acid etc, Luliconazole, an azole antifungal has nikkomycins, icofungipen fungicidal action against Trichophyton spe- Newer and Demcidin, macrocarpal C cies. It has a unique structure, as the imid- potential therapies azole moiety is incorporated into the ketene dithioacetate structure. Luliconazole is the Medical Management with Anti-Fungals (1) R-enantiomer, and has more potent antifungal activ- Various anti-fungal agents are available for a phy- ity than lanoconazole, which is a racemic mixture. The sician’s armamentarium. Systemic therapy should be strong clinical antifungal activity of luliconazole could considered for large lesions that do not clear even after be attributed to a combination of strong in vitro anti- repeated treatment using different topical agents. Unmet Need of new Topical Anti-Fungal Agent (2) Adequate treatment of cutaneous my- coses requires prolonged treatment for complete clearance. Non-compliance is common place among the patients, as ini- tial clinical improvements start to show; thereby resulting in a high rate of relapse in patients who were previously consid- ered cured; one of the biggest challenges in treating fungicidal infections. There arises a need for anti-fungal agents that attain their mycologic negativity even after short- term use. An ideal agent against superficial der- matophytosis would have a broad-spec- trum of activity, efficacy at low concentra- Figure 1: Illustration of mode of action of Luliconazole The Indian Practitioner q Vol.72 No.2. February 2019 43 Review Article fungal activity and favourable pharmacokinetic prop- severe tinea pedis and eight participants with moder- erties in the skin. ate to severe tinea cruris. The participants applied luli- Topical antifungals with potent anti-inflammatory conazole 1% cream once daily for 15 days. Luliconazole action like luliconazole may be a better alternative to plasma concentrations were measured on day 15. antifungal-steroid combination. Results varied little within the 24-hour interval. (3-5) The mean ± standard deviation of the maximum • Pharmacodynamic Profile concentration (C ) was 0.40 ± 0.76 ng/mL and 4.91 ± Luliconazole hinders ergosterol synthesis by inhib- max 2.51 ng/mL after the first dose, and 0.93 ± 1.23 ng/mL iting the enzyme lanosterol demethylase. Inhibition of and 7.36 ± 2.66 ng/mL after the final dose in partici- this enzyme decreases ergosterol levels, a constituent pants with either tinea pedis or tinea cruris. of fungal cell membranes, and a corresponding accu- mulation of lanosterol. The mean time to reach Cmax (Tmax) was 16.9 ± 9.39 hours after the first dose and 5.8 ± 7.61 hours after the Minimum Inhibitory Concentration (MIC) Comparison with final dose for the participants with tinea pedis, and different Anti-Fungal Agents (6-7) was 21.0 ± 5.55 hours after the first dose and 6.5 ± 8.25 In a study on the in vitro antifungal activity of luli- hours after the final dose for participants with tinea conazole against pathogenic fungi implicated in der- cruris. In participants with tinea pedis, exposure to lu- matomycoses, about 91 clinical isolates, consisting liconazole - as expressed by area under the concentra- of 59 Trichophyton rubrum isolates, 26 T. mentagro- tion time curve (AUC 0–24) - was 6.88 ± 14.50 ng*hr/ phytes isolates, 1 Epidermophyton floccosum isolate, mL after the first dose and 18.74 ± 27.05 ng*hr/mL after and 5 Candida albicans isolates were tested by the the final dose. Exposure to luliconazole, as expressed broth microdilution method, employing lanoconazole, by AUC 0 - 24 was 85.1 ± 43.69 ng*hr/mL after the first terbinafine, and bifonazole as reference drugs. dose and 121.74 ± 53.36 ng*hr/mL after the final dose The minimum inhibitory concentrations (MICs) of for participants with tinea cruris. luliconazole against T. rubrum and T. mentagrophytes • Dosage and Duration (3) were in the range of 0.00012–0.004µg/ml and 0.00024– Interdigital Tinea Pedis: 1% cream should be ap- 0.002µg/ml, respectively. The MIC 90 of luliconazole plied to the affected and immediate surrounding for both species were at 0.001 µg/ml. These values were area(s) once a day for two weeks. 4 times lower than lanoconazole, 30 times lower than Tinea Cruris and Tinea Corporis: 1% cream should terbinafine and 1000 times lower than bifonazole. be applied to the affected skin and immediate sur- • Pharmacokinetic Profile(3, 8-9) rounding area(s) once a day for one week. The pharmacokinetics of luliconazole 1% cream Therapeutic Efficacy were investigated in 12 participants with moderate to In Innovator