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Home , Eberconazole, Luliconazole, Pramiconazole

Review Article : Paradigm Shift in the Management of Topical Tinea Infections Dr Hardik Pathak

Abstract Luliconazole is an topical agent with a unique structure. Pre-clinical studies have dem- onstrated excellent activity against . Although luliconazole belongs to the 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 , and performed better than . 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 , up to 4 weeks of twice-daily treatment with , 1–2 weeks of twice-daily treatment with terbinafine, 4 weeks of once-daily application of and 4–6 weeks of once-daily treatment with . 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, , 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). 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 , , neum, lack of development of fungal re- Heterocyclic benzofuran sistance, low relapse rates, minimum side- effects, and low cost. Antimetabolite Luliconazole: Unique Topical Anti-Fungal Topical - , econazole, , Agent with Multiple Advantages (1-3) , , , , Luliconazole, also known as NND-502, sertaconazole, berconazole, luliconazole, is an imidazole antifungal first synthesized by Nihon Nohyaku Co Ltd (Osaka, Japan). Systemic - Japan approved Luliconazole 1% cream , (also topical), , in 2005 for tinea infection, followed by US , isavuconazole, posoconazole, , , Food and Drug Administration (USFDA) approval in November 2013 for interdigital Terbinafine, , naftifine tinea pedis, tinea cruris, and tinea corporis , , , 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 , , amorolfine, , 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 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 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 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 sponsored three phase-3 clinical trials, 616 subjects were exposed to lulicon- azole cream 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied lulicon- azole cream, 1% or vehicle cream once daily for 14 days or 7 days respectively to affected and adjacent areas.(3, 10) • Tinea Corporis / Cruris In a prospective, parallel-group study, 60 patients diagnosed with tin- ea corporis were alternately assigned to receive either terbinafine or lulicon- azole once daily for 2 weeks. Clinical examination and KOH microscopy on day 15 and day 30, revealed that the Table 2: in vitro MIC comparison between various anti-fungal agents in patients total composite score and KOH mount with dermatomycoses was negative by day15, with similar

44 The Indian Practitioner q Vol.72 No.2. February 2019 Review Article improvement in symptoms and signs in both groups durations with luliconazole cream 1% were evaluated (P.0.05). Luliconazole and terbinafine were equally ef- for treatment of tinea pedis (TP). fective in treating tinea corporis/cruris, when applied Participants with interdigital TP were randomized (10) once daily for two weeks. (N=147) and treated with either luliconazole or vehicle In India, a prospective, randomized, multicenter, for either 2 or 4 weeks. The primary efficacy end point open-label, parallel-group study was conducted in was the proportion of participants achieving complete adults aged 18–70 years with a clinical diagnosis and clearance 2 weeks following completion of treatment. at least positive KOH microscopy for tinea corporis In the 2-week active treatment group, complete clear- and tinea cruris. The patients were randomized into ance was achieved in 26.8% (11/41) of participants ver- three groups to receive: sertaconazole 2% cream (twice sus 9. 1% (2/22) in the 2-week vehicle group at 2-weeks daily for 4 weeks), terbinafine 1% cream (once daily for post-treatment. (14) 2 weeks), or luliconazole 1% cream (once daily for 2 In the 4-week active treatment group, 45.7% (16/35) weeks). By the end of the follow-ups, the mean total of the patients achieved complete clearance versus composite score for all clinical symptoms and signs of 10.0% (2/20) in the 4-week vehicle group at 2-weeks tinea infection (total of pruritus, erythema, vesicles, post-treatment. More importantly, the antifungal ef- and desquamation graded as 0 to 3 based on severity) fects of luliconazole persist for several weeks, resulting was 0 in the sertaconazole and luliconazole groups and in increased rates of mycological cure. (15) 0.05 in terbinafine group.(11) A multicenter, randomized, single-blind, two-way, In a different multicenter, randomized, open-label parallel-group study compared the clinical efficacy of comparative study from India, adult patients with tin- 1% luliconazole cream applied once daily for 2 weeks ea corporis / cruris / pedis were randomized to receive to bifonazole 1% cream applied once daily for 4 weeks. luliconazole, sertaconazole, amorolfine, eberconazole About 489 patients were randomized into groups for or terbinafine cream. Creams were applied once daily either luliconazole 1% or bifonazole 1%. In the lulicon- for one week in patients with tinea cruris/tinea corpo- azole group, the patients applied placebo cream for 2 ris and for 2 weeks in patients with tinea pedis. Efficacy weeks after 2 weeks of treatment with the active drug. as assessed by change in clinical signs and symptoms, Luliconazole 1% cream demonstrated superior ef- negative KOH microscopy were 93.3%, 86.6%, 83.3%, ficacy over bifonazole in achieving mycologic cure 80%, and 73.3% in the groups treated with sertacon- (negative culture), with 73% of patients found to be azole, luliconazole, amorolfine, terbinafine and - eber culture-negative in the luliconazole group in contrast conazole respectively.(12) with 50% of patients in the bifonazole group. The clini- A recently published, randomized, double-blind, cal and mycologic efficacy of short-term (2-week) treat- parallel-group, vehicle-controlled, multicenter study ment with luliconazole was found to be at par with the included 256 patients with a clinical diagnosis of tinea standard 4 weeks of treatment with bifonazole.(16) cruris confirmed on KOH microscopy and fungal cul- A multiclinic, randomized, double-blind, three- ture. Participants applied either 1% luliconazole cream way, parallel-group comparative study evaluated dif- or vehicle once daily for 7days. ferent strengths of luliconazole cream (1%, 0.5%, and Out of the patients, about 21.2% treated with luli- 0.1%) applied once daily for 2weeks and 213 partici- conazole and 4.4% treated with vehicle had complete pants with tinea pedis completed the study. clearance. Similarly, clinical cure (24.2% versus 6.6%), Rates for improvement of skin lesions in the groups mycologic cure (78.2% versus 45.1%), and effective treated with luliconazole 1%, 0.5%, or 0.1% cream as- treatment (43% versus 18.7%) rates were all signifi- sessed at week 4 were 90.5%, 91.0% and 95.8%, respec- cantly higher in luliconazole treated patients as com- tively. Achievement of mycologic negativity (by KOH pared with vehicle-treated patients. Luliconazole 1% microscopy) at week 4 was 79.7%, 76.1%, and 72.2% cream applied once daily for 7 days was concluded to and at week 6 (4 weeks after the end of topical treat- be more effective than vehicle for the treatment of tinea ment) was 87.7%, 94% and 88.9%, respectively. The cruris.(13) authors concluded that luliconazole 1% cream was an • Tinea Pedis effective treatment for tinea pedis, even when used in Luliconazole, a novel imidazole drug, is shown to for a short duration. (17) be as or more effective in vitro and in vivo than bifon- Another study included 147 patients with KOH and azole, terbinafine, and lanoconazole. Two treatment culture-confirmed interdigital tinea pedis and those

The Indian Practitioner q Vol.72 No.2. February 2019 45 Review Article were enrolled in a randomized, double-blind, vehicle- Publishers (P) Ltd. New Delhi.2013 controlled, Phase III trial of luliconazole 1% cream. The 6. Koga H et al. In vitro antifungal activity of luliconazole participants were randomized in a 2:2:1:1 ratio to 2 or against clinical isolates from patients with dermatomycoses. 4 week treatment with luliconazole 1% cream or ve- J Infect Chemother (2006) 12:163–165. hicle once daily. Complete clearance and mycological 7. Koga H et al. In vitro antifungal activities of luliconazole, a cure rates were measured at the second and the fourth new topical imidazole. Medical Mycology 2009; 47: 640-647. weeks post-treatment. Efficacy rates in both lulicon- 8. Gupta AK, Daigle D. A critical appraisal of once-daily topi- azole 1% groups were higher than vehicle when mea- cal luliconazole for the treatment of superficial fungal infec- tions. Infection and Drug Resistance 2016; 9: 1–6. sured at the second and the fourth weeks post-treat- (18) 9. Feng X et al. Efficacy and tolerability of luliconazole cream ment. There were no treatment-related AEs. 1% for dermatophytoses: A Meta-analysis. Journal of Safety Profile(3, 13, 17) Dermatology 2014; 41: 779–782. The most common adverse reactions observed in 10. Vidhya Lakshmi CP, Bengalorkar GM, Shiva Kumar V. clinical trials were application site reactions, which oc- Clinical efficacy of topical terbinafine versus topical- luli curred in less than 1% of subjects. Most adverse reac- conazole in treatment of tinea corporis/tinea cruris patients. British Journal of Pharmaceutical Research 2013; 3(4): 1001-1014. tions were mild in severity. 11. Jerajani H, Janaki C, Kumar S, Phiske M. Comparative as- Topical luliconazole cream in different strengths sessment of the efficacy and safety of sertaconazole (2%) were tolerated well in clinical studies. In general, ap- cream versus terbinafine cream (1%) versus luliconazole plication site reactions, itching, heat sensation, irrita- (1%) cream in patients with dermatophytoses: a pilot study. tion, redness & pruritus were reported in literature but Indian J Dermatol.2013; 58:34–38. none of the patients require discontinuation of thera- 12. Selvan A, Girisha G, Vijaybhaskar, Suthakaran R. py. No systemic events were reported in other trials. Comparative evaluation of newer topical anti-fungal agents in the treatment of superficial fungal infections (tinea or der- Conclusion matophytic). Int Res J Pharm 2013; 4:224–228. Luliconazole is a novel azole topical anti-fungal 13. Jones TM, Jarratt MT, Mendez-Moguel I et al. A randomized, with the addition of an imidazole moiety which aug- multicenter, double-blind, vehicle-controlled study evaluat- ments its ability to target filamentous fungi such as ing the efficacy and safety of luliconazole cream1% once dermatophytes. It was the first regulatory authority daily for 7 days in patients aged ≥ 12 years with tinea cruris. J Drugs Dermatol.2014; 13:32–38 approved topical azole antifungal agent mentioned 14. Jarratt M et al. Luliconazole for the treatment of interdigital to treat tinea cruris and tinea corporis with a 1-week, tinea pedis: A double­blind, Vehiclecontrolled­ study. Cutis once-daily treatment regimen. The antifungal effects 2013;91 (4):20310­ of luliconazole persisted for several weeks, resulting in 15. Gold MH, Olin JS. Once-daily luliconazole cream 1% for the increased rates of mycological cure. It is well tolerated treatment of interdigital tinea pedis. Expert Review of Anti- and has favourable safety profile. The most common infective Therapy 2015:1-17. adverse events were mild application site reactions. It 16. Watanabe S et al. A comparative clinical study between 2 is very much patient compliant due to its single time in weeks of luliconazole 1% cream treatment and 4 weeks of a day application. Till now, a mechanism of resistance bifonazole 1% cream treatment for tinea pedis. Mycoses 2006; to luliconazole has not been described. 49: 236–241. 17. Watanabe S, Takahashi H, Nishikawa T et al. Dose-finding References comparative study of 2weeks of luliconazole cream treat- 1. Sahoo AK, Mahajan R. Management of tinea corporis, tin- ment for tinea pedis – comparison between three groups ea cruris, and tinea pedis: A comprehensive review. Indian (1%, 0.5%, 0.1%) by a multicenter randomised double-blind Dermatol Online J 2016; 7:77-86 study. Mycoses 2007; 50: 35–40. 2. Khanna D, Bharti S. Luliconazole for the treatment of fungal 18. Jarratt M et al. Efficacy and safety of once-daily luliconazole infections: an evidence-based review. Core Evidence 2014:9 1% cream in patients ≥12 years of age with interdigital tinea 113–124. pedis: a phase 3, randomized, double-blind, vehicle-con- 3. LUZU label. Prescribing information http://www.access- trolled study. J Drugs Dermatol. 2014; 13(7):838-46. data.fda.gov/drugsatfda_docs/label/2013/204153s000lbl.pdf assessed on 30th December, 2018. 4. Brunton LL editor. Anti-fungal agents. In: Goodman & 9 Gilman’s - The Pharmacological Basis of Therapeutics. 12th edition. The McGraw-Hill publication. Newyork.2011. 5. Tripathi KD editor. Anti-fungal drugs. In: Essentials of Medical Pharmacology, 7th edition. Jaypee Brothers Medical

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