Luliconazole Retention in Stratum Corneum and Prevention of Fungal Infection in a Guinea Pig Tinea Pedis Model
January 2016 | Volume 15 | Issue 1 | Original Article | 104 | Copyright © January 2016
Hiroyasu Koga PhD,a Yasuko Nanjoh,a Tetsuo Toga PhD,a Radhakrishnan Pillai PhD,b William Jo PhD,b and Ryoji Tsuboi PhDc
aNihon Nohyaku Co., Ltd., Tokyo, Japan
bDow Pharmaceutical Sciences, a division of Valeant Pharmaceuticals North America, LLC, Petaluma, CA
cDepartment of Dermatology, Tokyo Medical University, Tokyo, Japan
OBJECTIVE: To compare drug concentrations in the stratum corneum following daily application of luliconazole and terbinafine cream in a guinea pig tinea pedis model.
METHODS: Luliconazole 1% cream or terbinafine 1% cream were topically applied once daily to hind limbs of guinea pigs for 14 days. Drug concentration in stratum corneum of plantar skin was measured by HPLC-UV on days 1, 3, 7, 10, and 14. Separately, creams were applied daily for 5 days to the hind limbs of guinea pigs and skin drug release determined. In addition, drug retention in the stratum corneum was assessed by infecting guinea pigs with Trichophyton mentagrophytes, 14 and 21 days after a single application of luliconazole or terbinafine creams.
RESULTS: Luliconazole stratum corneum concentrations were higher than those of terbinafine throughout the study. Concentrations of luliconazole and terbinafine were 71.6μg/g and 36.6μg/g, respectively, after a single application (P<.05), reaching steady state after 10 days. Cumulative release of luliconazole from the stratum corneum was 4.5 times greater than with terbinafine. Unlike terbinafine, no fungal invasion of the stratum corneum was seen 14 days post-treatment with luliconazole.
CONCLUSIONS: Drug concentrations of luliconazole in the stratum corneum and subsequent release are greater than those achieved with terbinafine and may contribute to clinical efficacy. Luliconazole may also provide greater protection against disease recurrence. J Drugs Dermatol.
Cutaneous fungal infections are very common, typically involving the skin, hair and nails, and are most often caused by dermatophytes.1 Tinea pedis is the most prevalent, where dermatophytes infect, invade and persist in the stratum corneum because they require keratin for growth.2,3 As a result, topical antifungals are the preferred therapy.4,5 In addition to exhibiting potent antifungal activity, it is important that these drugs achieve high concentrations in the stratum corneum and remain in high concentrations within the infected stratum corneum for a prolonged period.
Luliconazole cream 1% is a broad-spectrum imidazole antifungal
that has been shown to be efficacious and well tolerated when administered once daily for 14 days in patients with interdigital
tinea pedis.6,7 It was approved in the United States for treatment of tinea pedis, tinea corporis, and tinea cruris in 2013, and in Japan since 2005, where it is also approved for candidiasis
and tinea versicolor.
In an in vivo guinea pig model, luliconazole was shown to have similar efficacy to terbinafine, with superior efficacy to lanoconazole
(P=.003).8 However, in this model (produced by infecting shaved dorsal hairy skin with Trichophyton mentagrophytes
[T. mentagrophytes]) there is spontaneous healing within 2-3 weeks of infection that can interfere with the evaluation.9
Relapse or re-infection is not uncommon in patients with tinea pedis.10 The in vivo anti-mycotic activity of luliconazole has also been studied using the guinea pig model developed by Fujita and Matsuyama,11,12 where T. mentagrophytes infection of the foot is sustained for a long period without spontaneous regression, and the clinical and histopathological features resemble those of naturally occurring tinea pedis in humans.13 Topical application of luliconazole for one week in this tinea pedis model achieved 100% mycologic cure in plantar skin samples taken at 1, 6, and 16 weeks post-treatment, suggesting that short-term treatment with luliconazole
may have good clinical efficacy.14 The short-term application of luliconazole 1% cream was also studied in both tinea pedis (7- and 14-day treatment) and tinea corporis guinea pig models. Luliconazole completely eradicated T. mentaprophytes in half the time (or less) than that required for terbinafine.15
In our study, we used the same tinea pedis guinea pig model to investigate the deposition of luliconazole and terbinafine in stratum corneum, subsequent drug release, and skin retention and protection against fungal invasion.