mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Review article
Luliconazole: a review of a new antifungal agent for the topical treatment of onychomycosis Richard K. Scher,1 Norifumi Nakamura2 and Amir Tavakkol2 1
Weill Cornell Medical College, Cornell Medical School, New York, NY, USA and 2Topica Pharmaceuticals, Inc., Los Altos, CA, USA
Summary
Luliconazole is a novel, broad-spectrum, imidazole antifungal under development in the USA as a treatment for dermatophytic skin and nail infections. In vitro, luliconazole is one of the most potent antifungal agents against filamentous fungi including dermatophytes. Luliconazole has been formulated in a 10% solution with unique molecular properties, which allow it to penetrate the nail plate and rapidly achieve fungicidal levels in the nail unit. These properties make luliconazole a potent compound in the treatment of onychomycosis. This article reviews the development of luliconazole solution, 10% its molecular properties, preclinical and clinical data and its future perspectives for the treatment of fungal infections.
Key words: Luliconazole, antifungal, onychomycosis, topical, dermatophyte, Trichophyton rubrum.
Introduction Luliconazole is a novel, broad-spectrum, imidazole antifungal, which inhibits sterol 14a-demethylase thereby interfering with ergosterol biosynthesis.1,2 It has a unique chemical structure (Fig. 1), with an imidazole moiety incorporated into the ketone dithioacetate structure.3 Through this modification, high potency against filamentous fungi including dermatophytes has been achieved, while maintaining the broad antifungal spectrum of an imidazole.3 Luliconazole was originally developed in Japan as a topical antifungal drug for the treatment of superficial dermatomycosis and received marketing approval by Japanese health authorities in 20053,4 as a 1% cream, 1% solution and 1% ointment for the treatment of superficial mycoses including dermatophytosis, candidiasis and pityriasis versicolor.3,5,6 To date, approximately 12 million patients have received treatment in Japan where luliconazole is the Correspondence: A. Tavakkol, Topica Pharmaceuticals, Inc., 4300 El Camino Real, Suite 101, Los Altos, CA 94022, USA. Tel.: +1 650 209 3717. Fax: +1 650 644 0173. E-mail: [email protected] Submitted for publication 25 November 2013 Accepted for publication 11 December 2013
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
leading prescribed topical prescription antifungal treatment. Based on the favourable efficacy and safety profile observed in clinical studies and postmarketing surveillance of luliconazole in Japan,5,6 efforts are underway in the USA to develop luliconazole for onychomycosis. In the USA, the Food and Drug Administration has very recently approved luliconazole, 1% cream for the treatment of interdigital tinea pedis, tinea cruris and tinea corporis, caused by the organisms Trichophyton rubrum and Epidermophyton floccosum. This review article will focus on USA development of luliconazole solution, 10% for treatment of distal subungual onychomycosis, which continues to be a challenging disease with significant unmet medical need and few treatment options.
Onychomycosis Onychomycosis represents up to 50% of all nail disorders,7 with an estimated prevalence of 10% in the general population and up to 50% in people aged over 60 years.8 Onychomycosis may cause major disability and pain (Fig. 2), and may have a negative impact on a patient’s well-being and self-esteem.9 There is a high incidence of onychomycosis in patients with diabetes; these patients should be treated promptly as onychomycosis may cause severe complications (Fig. 3).10
doi:10.1111/myc.12168
R. K. Scher et al.
Figure 1 Chemical structure of luliconazole: (-)-(E)-[4-(2,4-di-
chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile.
treat with failure, reinfection and relapse very common.12–14 Orally administered drugs are considered to be the most effective treatment for onychomycosis, with between 14% and 38% complete cure rates; however, their uses are limited by safety concerns (e.g. require blood draws to monitor liver enzymes for hepatotoxicity and monitoring for drug–drug interactions) due to systemic exposure.13,15 Topical treatments are safer but require patient compliance to be effective.16 In spite of the potential advantages of local therapy, currently approved medications applied directly to the nail are associated with very low complete cure rates.15 Accordingly, an effective, safe and convenient topical treatment for onychomycosis would fill an important unmet need.17,18
Luliconazole’s fungicidal and fungistatic activity
Figure 2 A pincer toenail with onychomycosis; typically painful
and causes difficulty in walking or wearing shoes.
Luliconazole has demonstrated fungicidal activity at very low levels (MIC90 0.001 lg ml 1 Trichophyton rubrum) through inhibition of ergosterol biosynthesis as well as fungistatic activity through inhibition of extracellular protease secretion 19 at levels below the drug’s MIC90 levels required for fungicidal effect.1,2,4,20–23 In both in vitro and in vivo studies, luliconazole has demonstrated potent and broad-spectrum activity against dermatophyte and non-dermatophyte pathogens, with reported MICs considerably lower than those of other antifungal drugs including terbinafine, bifonazole, clotrimazole, miconazole and amorolfine hydrochloride (Table 1).24
Luliconazole’s properties
Figure 3 Severe dystrophic toenail onychomycosis and poor
peripheral circulation in a patient with diabetes.
Dermatophytes account for approximately 90% of onychomycosis cases; Trichophyton rubrum, followed by T. mentagrophytes, are the most common pathogens.7–9,11,12 Onychomycosis is generally difficult to
390
Luliconazole has a low binding affinity for keratin, the main component of the nail plate, thereby allowing the drug to be readily released from the nail plate’s keratin matrix to cross into the nail bed. Furthermore, luliconazole’s potency is unaffected by keratin25; this is in contrast to many azoles, which have a significant reduction in potency in the presence of keratin.26 Some topical onychomycosis formulations have utilised lacquers to deliver the active drug which may also limit their effectiveness to reach the site of infection in the nail bed,7,11,27 thus reducing their effectiveness. These properties make luliconazole a compelling candidate for the topical treatment of onychomycosis.
Safety and tolerability Luliconazole has been reported to be safe and well tolerated by human subjects in single- and repeated-
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
Luliconazole in onychomycosis
Table 1 Comparison of published minimum inhibitory concentrations (MIC) of luliconazole and other antifungal agents against dermatophyte pathogens and Candida albicans.24
Trichophyton rubrum T. mentagrophytes1 T. tonsurans2 Trichophyton spp.1 Candida albicans1
1
Luliconazole
Terbinafine
Bifonazole
Clotrimazole
Miconazole
Amorolfine hydrochloride
0.00024 0.002 0.0049 0.002 0.13
0.0078 0.016 0.0078 0.016 4
0.13 1 1 1 1
0.063 0.25 0.25 0.25 0.016
0.13 2 1 1 0.063
0.031 0.25 0.063 0.25 2
1
MIC90 values.
2
application studies.5,17,28,29 Skin irritation indices have been reported to be within the range specified for a safe product.5 No toxicity issues have been reported in guinea pig model studies of tinea pedis induced with T. mentagrophytes.1,3,30 In a 39-week dermal toxicity study in Gottingen Minipigsâ; Marshall BioResources, North Rose, NY, USA, luliconazole solution, 10% was well tolerated with no treatment-related adverse events when applied dermally up to 100 mg kg 1 day 1. Toxicokinetic analysis also showed that luliconazole area under the curve (AUC) values in the high-dose (100 mg kg 1 day 1) minipig group were up to 1200-fold higher than human AUC value observed in the human PK study. Based on the above results, the no observed adverse effect level for both systemic and local toxicity was 100 mg kg 1 day 1 following 39 weeks of daily dermal application of luliconazole solution, 10% to Gottingen Minipigsâ (data on file).
Activity in preclinical models of onychomycosis Luliconazole’s physical properties and its potent activity against Trichophyton spp. and other dermatophytes have led to the development of a novel and rapiddelivery formulation to treat onychomycosis. Luliconazole solution, 10% has been shown to penetrate healthy human toenails in an in vitro study.25 Cumulative amounts of luliconazole penetrating the nail plate per surface area were used to calculate the formulation’s flux rate (where flux is measured as the amount of drug delivered area 1 time 1). The drug’s flux rate was then used to calculate the topical efficacy coefficient 31 as a means to predict theoretical clinical efficacy.25 Therapeutic levels of luliconazole across full thickness human nail plate were achieved within 7 days of daily dosing with a flux rate of 107.75 lg cm 2 day 1 and an efficacy coefficient (flux/MIC90) of 1.1 9 105. These results suggest a high potential of clinical effectiveness for luliconazole
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
Cumula ve amount of luliconazole per unit area (μg cm–2)
MIC50 values.
3000.00
2500.00
Luliconazole 7 day Luliconazole 21 day
2000.00
1500.00
1000.00
500.00
0.00 0
7
14
21
Time (days)
Figure 4 Cumulative amount of luliconazole permeated
(lg cm 2) after daily dosing for 7 and 21 days [mean standard error of the mean (SEM), n = 6].
Table 2 Flux and efficacy coefficient of luliconazole. Experiments with 10% luliconazole solution 7 day application 21 day application 0–21 days 7–21 days
Flux (lg cm
2
day 1)
Efficacy coefficient (flux/MIC90)
107.75 27.21
1.1 9 105
81.10 43.60 98.95 58.25
8.1 9 104 9.9 9 104
The amount of luliconazole permeated per unit area per day after continuous dosing for 7 and 21 days are shown as mean standard error of the mean (SEM), n = 6. MIC90 = 0.001 lg ml
1
against Trichophyton rubrum.
solution, 10% in treating onychomycosis (Fig. 4, Table 2).25 In another study, an in vitro T. rubruminfected nail model, the same 10% solution formulation crossed the nail bed rapidly eradicating the fungal load within 21 days of application.32 Therapeutic levels of luliconazole across full thickness human nails were achieved within 7 days of daily dosing.32
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Clinical experience in onychomycosis An open-label pharmacokinetic and safety study was conducted in 24 patients with moderate–to-severe distal subungual onychomycosis treated with luliconazole solution, 10% 200 ll day 1, which was twice the anticipated clinical dose, daily for 29 days.17 In this study, luliconazole showed very low systemic absorption and excellent local tolerability with no evidence of laboratory abnormalities or subject discontinuation,33 with plasma concentrations near or below the lower limit of quantification (0.05 ng ml 1).17 In contrast, median nail concentration of luliconazole 7 days after the last application was 35 mg g 1;17 thousands of times greater than the MIC90 of T. rubrum and T. mentagrophytes (0.001 lg ml 1).4 Very low levels of luliconazole were measurable in plasma up to 7 days after the last application, indicating that the nail plate may serve as a reservoir allowing its slow release into the nail bed.17 This nail reservoir may potentially allow for the development of more convenient dosing regimens to enhance compliance and improve patient outcomes.
Current research Based on the results of the phase 1/2a clinical research with luliconazole solution, 10%, a randomised, double-blind, phase 2/3 study was initiated in 2012 in the USA. The study is currently ongoing and will determine the efficacy and safety of luliconazole solution, 10%, in the treatment of adults with mild-to-moderate distal lateral subungual onychomycosis of the toenail (NCT01431820). Patients were randomised into two dosing regimens (a high-dose and a low-dose regimen) of luliconazole solution, 10% and matching vehicle control groups. They were evaluated at baseline and will be reevaluated every 4 weeks for 48 weeks, with an additional 4 weeks off drug. The primary efficacy variable is the proportion of subjects achieving complete cure of the target great toenail at Week 52. The study enrolment has been completed, with 334 patients in the study. The results of the study are expected in the second half of 2014.
keratin, robust activity in preclinical models and safety profile in phase 1/2a testing make it a promising candidate for the topical treatment of onychomycosis. In the ongoing phase 2b/3 study, the topical application of luliconazole solution, 10% or its vehicle has shown excellent local tolerability to date, a clinical laboratory safety profile consistent with low systemic absorption, and an unremarkable safety profile based on the number of adverse events leading to study discontinuation. Results of a phase 2/3 trial are anticipated in the second half of 2014.
Acknowledgments Editorial assistance to the authors’ original work was provided by Sheena Hunt, PhD. This assistance was funded by Topica Pharmaceuticals Inc. The authors thank Dr B Sigurgeirsson and Dr R Pollak for providing the onychomycosis photographs presented in the report. Dr RK Scher is the Professor of Clinical Dermatology at The Department of Dermatology, Weill Cornell Medical College, Cornell Medical Center, New York, NY and is a consultant, speaker and investigator for multiple pharmaceutical companies including Topica Pharmaceuticals, Inc. Drs A Tavakkol and N Nakamura are employees of Topica Pharmaceuticals, Inc.
References 1
2
3
4
5
6
Conclusions
7
Luliconazole is a highly potent, safe and well-studied molecule in the clinical research setting and in the postmarketing environment. The molecule’s potent in vitro antifungal activity, low binding affinity to
8
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9
Uchida K, Tanaka T, Yamaguchi H. Achievement of complete mycological cure by topical antifungal agent NND-502 in guinea pig model of tinea pedis. Microbiol Immunol 2003; 47: 143–6. Niwano Y, Koga H, Kodama H, Kanai K, Miyazaki T, Yamaguchi H. Inhibition of sterol 14 alpha-demethylation of Candida albicans with NND-502, a novel optically active imidazole antimycotic agent. Med Mycol 1999; 37: 351–5. Koga H, Nanjoh Y, Kaneda H, Yamaguchi H, Tsuboi R. Short-term therapy with luliconazole, a novel topical antifungal imidazole, in guinea pig models of tinea corporis and tinea pedis. Antimicrob Agents Chemother 2012; 56: 3138–43. Koga H, Tsuji Y, Inoue K et al. In vitro antifungal activity of luliconazole against clinical isolates from patients with dermatomycoses. J Infect Chemother 2006; 12: 163–5. Watanabe S, Takahashi H, Nishikawa T et al. A comparative clinical study between 2 weeks of luliconazole 1% cream treatment and 4 weeks of bifonazole 1% cream treatment for tinea pedis. Mycoses 2006; 49: 236–41. Watanabe S, Takahashi H, Nishikawa T et al. Dose-finding comparative study of 2 weeks of luliconazole cream treatment for tinea pedis–comparison between three groups (1%, 0.5%, 0.1%) by a multicenter randomised double-blind study. Mycoses 2007; 50: 35–40. Dahdah MK, Scher RK. Onychomycosis — an overview. US Dermatol Rev 2006; 1–4. Thomas J, Jacobson GA, Narkowicz CK, Peterson GM, Burnet H, Sharpe C. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther 2010; 35: 497–519. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol 1997; 36: 754–6.
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10 11 12
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15 16 17
18 19
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Pollak RA, Tavakkol A. Onychomycosis in diabetic patients: to treat or not to treat. Podiatry Management 2005; 3: 111–7. Elewski BE. Onychomycosis: pathogenesis, diagnosis and management. Clin Microbiol Rev 1998; 11: 415–29. Ghannoum MA, Hajjeh RA, Scher R et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution and antifungal susceptibility patterns. J Am Acad Dermatol 2000; 43: 641–8. Alley MR, Baker SJ, Beutner KR, Plattner J. Recent progress on the topical therapy of onychomycosis. Exp Opin Investig Drugs 2007; 16: 157–67. Scher RK, Rich P, Pariser D, Elewski B. The epidemiology, etiology and pathophysiology of onychomycosis. Semin Cutan Med Surg 2013; 32: S2–S4. Loo DS. Systemic antifungal agents: an update of established and new therapies. Adv Dermatol 2006; 22: 101–24. Shivakumar HN, Juluri A, Desai BG, Murthy SN. Ungual and transungual drug delivery. Drug Dev Ind Pharm 2012; 38: 901–11. Jones T, Tavakkol A. Safety and tolerability of luliconazole solution 10-percent in patients with moderate to severe distal subungual onychomycosis. Antimicrob Agents Chemother 2013; 57: 2684–9. Lipner S, Scher R. Onychomycosis update. Cutis 2014; (in press). Koga H, Toga T, Nanjoh Y, Tsuboi R, Yamaguchi H. The durable effect of luliconazole in a guinea pig tinea pedis model. Poster presented at the International Society for Human and Animal Mycology (ISHAM) Congress; May 25–29, Tokyo, Japan, 2009. Niwano Y, Kuzuhara N, Kodama H, Yoshida M, Miyazaki T, Yamaguchi H. In vitro and in vivo antidermatophyte activities of NND-502, a novel optically active imidazole antimycotic agent. Antimicrob Agents Chemother 1998; 42: 967–70. Niwano Y, Kuzuhara N, Goto Y et al. Efficacy of NND-502, a novel imidazole antimycotic agent, in experimental models of Candida albicans and Aspergillus fumigatus infections. Int J Antimicrob Agents 1999; 12: 221–8. Uchida K, Nishiyama Y, Yamaguchi H. In vitro antifungal activity of luliconazole (NND-502), a novel imidazole antifungal agent. J Infect Chemother 2004; 10: 216–9. Uchida K, Nishiyama Y, Tanaka T, Yamaguchi H. In vitro activity of novel imidazole antifungal agent NND-502 against Malassezia species. Int J Antimicro Agents 2003; 21: 234–8.
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24
25
26
27 28
29
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31
32
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Koga H, Nanjoh Y, Makimura K, Tsuboi R. In vitro antifungal activities of luliconazole, a new topical imidazole. Med Mycol 2009; 47: 640–7. Brown M, Turner R, Nakamura N. Nail permeation and depth profiling of luliconazole, a novel imidazole antifungal agent, for the topical treatment of onychomycosis. Poster presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 10–13, Denver, CO, USA, 2013. Sobue S, Sekiguchi K, Nabeshima T. Intracutaneous distributions of fluconazole, itraconazole, and griseofulvin in Guinea pigs and binding to human stratum corneum. Antimicrob Agents Chemother 2004; 48: 216–23. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother 2012; 13: 1131–42. Jarratt M, Jones T, Kempers S et al. Luliconazole for the treatment of the interdigital tinea pedis: a double-blind, vehicle-controlled study. Cutis 2013; 91: 203–10. Jerajani H, Janaki C, Kumar S, Phiske M. Comparative assessment of the efficacy and safety of sertaconazole (2%) cream versus terbinafine cream (1%) versus luliconazole (1%) cream in patients with dermatophytoses: a pilot study. Indian J Dermatol 2013; 58: 34–38. Ghannoum MA, Long L, Kim HG, Cirino AJ, Miller AR, Mallefet P. Efficacy of terbinafine compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis in a guinea pig model. Med Mycol 2010; 48: 491–7. Mertin D, Lippold BC. In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: prediction of the penetration rate of antimycotics through the nail plate and their efficacy. J Pharm Pharmacol 1997; 49: 866–72. Brown M, Turner R, Nakamura N. In vitro fungicidal activity of luliconazole in an infected nail model using full thickness human toe nails and T. Rubrum. Poster presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 10–13, Denver, CO, USA, 2013. Jones T, Tavakkol A. Results of a Phase 1/2a maximal use pharmacokinetic (PK) study of Luliconazole Solution, 10% in subjects with moderate to severe distal subungual onychomycosis (DSO). Poster 5294 presented at the 70th annual meeting of the American Academy of Dermatology (AAD); March 16–20, San Diego, CA, USA, 2012.
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Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Review article
Luliconazole: a review of a new antifungal agent for the topical treatment of onychomycosis Richard K. Scher,1 Norifumi Nakamura2 and Amir Tavakkol2 1
Weill Cornell Medical College, Cornell Medical School, New York, NY, USA and 2Topica Pharmaceuticals, Inc., Los Altos, CA, USA
Summary
Luliconazole is a novel, broad-spectrum, imidazole antifungal under development in the USA as a treatment for dermatophytic skin and nail infections. In vitro, luliconazole is one of the most potent antifungal agents against filamentous fungi including dermatophytes. Luliconazole has been formulated in a 10% solution with unique molecular properties, which allow it to penetrate the nail plate and rapidly achieve fungicidal levels in the nail unit. These properties make luliconazole a potent compound in the treatment of onychomycosis. This article reviews the development of luliconazole solution, 10% its molecular properties, preclinical and clinical data and its future perspectives for the treatment of fungal infections.
Key words: Luliconazole, antifungal, onychomycosis, topical, dermatophyte, Trichophyton rubrum.
Introduction Luliconazole is a novel, broad-spectrum, imidazole antifungal, which inhibits sterol 14a-demethylase thereby interfering with ergosterol biosynthesis.1,2 It has a unique chemical structure (Fig. 1), with an imidazole moiety incorporated into the ketone dithioacetate structure.3 Through this modification, high potency against filamentous fungi including dermatophytes has been achieved, while maintaining the broad antifungal spectrum of an imidazole.3 Luliconazole was originally developed in Japan as a topical antifungal drug for the treatment of superficial dermatomycosis and received marketing approval by Japanese health authorities in 20053,4 as a 1% cream, 1% solution and 1% ointment for the treatment of superficial mycoses including dermatophytosis, candidiasis and pityriasis versicolor.3,5,6 To date, approximately 12 million patients have received treatment in Japan where luliconazole is the Correspondence: A. Tavakkol, Topica Pharmaceuticals, Inc., 4300 El Camino Real, Suite 101, Los Altos, CA 94022, USA. Tel.: +1 650 209 3717. Fax: +1 650 644 0173. E-mail: [email protected] Submitted for publication 25 November 2013 Accepted for publication 11 December 2013
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
leading prescribed topical prescription antifungal treatment. Based on the favourable efficacy and safety profile observed in clinical studies and postmarketing surveillance of luliconazole in Japan,5,6 efforts are underway in the USA to develop luliconazole for onychomycosis. In the USA, the Food and Drug Administration has very recently approved luliconazole, 1% cream for the treatment of interdigital tinea pedis, tinea cruris and tinea corporis, caused by the organisms Trichophyton rubrum and Epidermophyton floccosum. This review article will focus on USA development of luliconazole solution, 10% for treatment of distal subungual onychomycosis, which continues to be a challenging disease with significant unmet medical need and few treatment options.
Onychomycosis Onychomycosis represents up to 50% of all nail disorders,7 with an estimated prevalence of 10% in the general population and up to 50% in people aged over 60 years.8 Onychomycosis may cause major disability and pain (Fig. 2), and may have a negative impact on a patient’s well-being and self-esteem.9 There is a high incidence of onychomycosis in patients with diabetes; these patients should be treated promptly as onychomycosis may cause severe complications (Fig. 3).10
doi:10.1111/myc.12168
R. K. Scher et al.
Figure 1 Chemical structure of luliconazole: (-)-(E)-[4-(2,4-di-
chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile.
treat with failure, reinfection and relapse very common.12–14 Orally administered drugs are considered to be the most effective treatment for onychomycosis, with between 14% and 38% complete cure rates; however, their uses are limited by safety concerns (e.g. require blood draws to monitor liver enzymes for hepatotoxicity and monitoring for drug–drug interactions) due to systemic exposure.13,15 Topical treatments are safer but require patient compliance to be effective.16 In spite of the potential advantages of local therapy, currently approved medications applied directly to the nail are associated with very low complete cure rates.15 Accordingly, an effective, safe and convenient topical treatment for onychomycosis would fill an important unmet need.17,18
Luliconazole’s fungicidal and fungistatic activity
Figure 2 A pincer toenail with onychomycosis; typically painful
and causes difficulty in walking or wearing shoes.
Luliconazole has demonstrated fungicidal activity at very low levels (MIC90 0.001 lg ml 1 Trichophyton rubrum) through inhibition of ergosterol biosynthesis as well as fungistatic activity through inhibition of extracellular protease secretion 19 at levels below the drug’s MIC90 levels required for fungicidal effect.1,2,4,20–23 In both in vitro and in vivo studies, luliconazole has demonstrated potent and broad-spectrum activity against dermatophyte and non-dermatophyte pathogens, with reported MICs considerably lower than those of other antifungal drugs including terbinafine, bifonazole, clotrimazole, miconazole and amorolfine hydrochloride (Table 1).24
Luliconazole’s properties
Figure 3 Severe dystrophic toenail onychomycosis and poor
peripheral circulation in a patient with diabetes.
Dermatophytes account for approximately 90% of onychomycosis cases; Trichophyton rubrum, followed by T. mentagrophytes, are the most common pathogens.7–9,11,12 Onychomycosis is generally difficult to
390
Luliconazole has a low binding affinity for keratin, the main component of the nail plate, thereby allowing the drug to be readily released from the nail plate’s keratin matrix to cross into the nail bed. Furthermore, luliconazole’s potency is unaffected by keratin25; this is in contrast to many azoles, which have a significant reduction in potency in the presence of keratin.26 Some topical onychomycosis formulations have utilised lacquers to deliver the active drug which may also limit their effectiveness to reach the site of infection in the nail bed,7,11,27 thus reducing their effectiveness. These properties make luliconazole a compelling candidate for the topical treatment of onychomycosis.
Safety and tolerability Luliconazole has been reported to be safe and well tolerated by human subjects in single- and repeated-
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
Luliconazole in onychomycosis
Table 1 Comparison of published minimum inhibitory concentrations (MIC) of luliconazole and other antifungal agents against dermatophyte pathogens and Candida albicans.24
Trichophyton rubrum T. mentagrophytes1 T. tonsurans2 Trichophyton spp.1 Candida albicans1
1
Luliconazole
Terbinafine
Bifonazole
Clotrimazole
Miconazole
Amorolfine hydrochloride
0.00024 0.002 0.0049 0.002 0.13
0.0078 0.016 0.0078 0.016 4
0.13 1 1 1 1
0.063 0.25 0.25 0.25 0.016
0.13 2 1 1 0.063
0.031 0.25 0.063 0.25 2
1
MIC90 values.
2
application studies.5,17,28,29 Skin irritation indices have been reported to be within the range specified for a safe product.5 No toxicity issues have been reported in guinea pig model studies of tinea pedis induced with T. mentagrophytes.1,3,30 In a 39-week dermal toxicity study in Gottingen Minipigsâ; Marshall BioResources, North Rose, NY, USA, luliconazole solution, 10% was well tolerated with no treatment-related adverse events when applied dermally up to 100 mg kg 1 day 1. Toxicokinetic analysis also showed that luliconazole area under the curve (AUC) values in the high-dose (100 mg kg 1 day 1) minipig group were up to 1200-fold higher than human AUC value observed in the human PK study. Based on the above results, the no observed adverse effect level for both systemic and local toxicity was 100 mg kg 1 day 1 following 39 weeks of daily dermal application of luliconazole solution, 10% to Gottingen Minipigsâ (data on file).
Activity in preclinical models of onychomycosis Luliconazole’s physical properties and its potent activity against Trichophyton spp. and other dermatophytes have led to the development of a novel and rapiddelivery formulation to treat onychomycosis. Luliconazole solution, 10% has been shown to penetrate healthy human toenails in an in vitro study.25 Cumulative amounts of luliconazole penetrating the nail plate per surface area were used to calculate the formulation’s flux rate (where flux is measured as the amount of drug delivered area 1 time 1). The drug’s flux rate was then used to calculate the topical efficacy coefficient 31 as a means to predict theoretical clinical efficacy.25 Therapeutic levels of luliconazole across full thickness human nail plate were achieved within 7 days of daily dosing with a flux rate of 107.75 lg cm 2 day 1 and an efficacy coefficient (flux/MIC90) of 1.1 9 105. These results suggest a high potential of clinical effectiveness for luliconazole
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 389–393
Cumula ve amount of luliconazole per unit area (μg cm–2)
MIC50 values.
3000.00
2500.00
Luliconazole 7 day Luliconazole 21 day
2000.00
1500.00
1000.00
500.00
0.00 0
7
14
21
Time (days)
Figure 4 Cumulative amount of luliconazole permeated
(lg cm 2) after daily dosing for 7 and 21 days [mean standard error of the mean (SEM), n = 6].
Table 2 Flux and efficacy coefficient of luliconazole. Experiments with 10% luliconazole solution 7 day application 21 day application 0–21 days 7–21 days
Flux (lg cm
2
day 1)
Efficacy coefficient (flux/MIC90)
107.75 27.21
1.1 9 105
81.10 43.60 98.95 58.25
8.1 9 104 9.9 9 104
The amount of luliconazole permeated per unit area per day after continuous dosing for 7 and 21 days are shown as mean standard error of the mean (SEM), n = 6. MIC90 = 0.001 lg ml
1
against Trichophyton rubrum.
solution, 10% in treating onychomycosis (Fig. 4, Table 2).25 In another study, an in vitro T. rubruminfected nail model, the same 10% solution formulation crossed the nail bed rapidly eradicating the fungal load within 21 days of application.32 Therapeutic levels of luliconazole across full thickness human nails were achieved within 7 days of daily dosing.32
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Clinical experience in onychomycosis An open-label pharmacokinetic and safety study was conducted in 24 patients with moderate–to-severe distal subungual onychomycosis treated with luliconazole solution, 10% 200 ll day 1, which was twice the anticipated clinical dose, daily for 29 days.17 In this study, luliconazole showed very low systemic absorption and excellent local tolerability with no evidence of laboratory abnormalities or subject discontinuation,33 with plasma concentrations near or below the lower limit of quantification (0.05 ng ml 1).17 In contrast, median nail concentration of luliconazole 7 days after the last application was 35 mg g 1;17 thousands of times greater than the MIC90 of T. rubrum and T. mentagrophytes (0.001 lg ml 1).4 Very low levels of luliconazole were measurable in plasma up to 7 days after the last application, indicating that the nail plate may serve as a reservoir allowing its slow release into the nail bed.17 This nail reservoir may potentially allow for the development of more convenient dosing regimens to enhance compliance and improve patient outcomes.
Current research Based on the results of the phase 1/2a clinical research with luliconazole solution, 10%, a randomised, double-blind, phase 2/3 study was initiated in 2012 in the USA. The study is currently ongoing and will determine the efficacy and safety of luliconazole solution, 10%, in the treatment of adults with mild-to-moderate distal lateral subungual onychomycosis of the toenail (NCT01431820). Patients were randomised into two dosing regimens (a high-dose and a low-dose regimen) of luliconazole solution, 10% and matching vehicle control groups. They were evaluated at baseline and will be reevaluated every 4 weeks for 48 weeks, with an additional 4 weeks off drug. The primary efficacy variable is the proportion of subjects achieving complete cure of the target great toenail at Week 52. The study enrolment has been completed, with 334 patients in the study. The results of the study are expected in the second half of 2014.
keratin, robust activity in preclinical models and safety profile in phase 1/2a testing make it a promising candidate for the topical treatment of onychomycosis. In the ongoing phase 2b/3 study, the topical application of luliconazole solution, 10% or its vehicle has shown excellent local tolerability to date, a clinical laboratory safety profile consistent with low systemic absorption, and an unremarkable safety profile based on the number of adverse events leading to study discontinuation. Results of a phase 2/3 trial are anticipated in the second half of 2014.
Acknowledgments Editorial assistance to the authors’ original work was provided by Sheena Hunt, PhD. This assistance was funded by Topica Pharmaceuticals Inc. The authors thank Dr B Sigurgeirsson and Dr R Pollak for providing the onychomycosis photographs presented in the report. Dr RK Scher is the Professor of Clinical Dermatology at The Department of Dermatology, Weill Cornell Medical College, Cornell Medical Center, New York, NY and is a consultant, speaker and investigator for multiple pharmaceutical companies including Topica Pharmaceuticals, Inc. Drs A Tavakkol and N Nakamura are employees of Topica Pharmaceuticals, Inc.
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Luliconazole is a highly potent, safe and well-studied molecule in the clinical research setting and in the postmarketing environment. The molecule’s potent in vitro antifungal activity, low binding affinity to
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