Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

Onychomycosis is a common fungal nail infection in adults that is difficult to treat. The in vitro antifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs against T. rubrum and T. mentagrophytes ranged from <0.002 to 0.06 g/ml, with 90% of isolates inhibited (MIC 90 ) at 0.008 and 0.015 g/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from <0.0005 to >0.25 g/ml, with 50% of isolates inhibited (MIC 50 ) by 0.001 and 0.004 g/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13 T. rubrum toenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon, and Candida and compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4-dimethylsterols and 4␣-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14␣-demethylase inhibition, leading to secondary degenerative changes. Ergosterol is an important structural component of fungal cell membranes, maintaining membrane fluidity and a permeability barrier, and is essential for fungal cell viability (1-3). Several classes of antifungal drugs target ergosterol biosynthesis. Among these, triazole antifungals (e.g., itraconazole) and imidazole antifungals (e.g., clotrimazole and miconazole) inhibit sterol 14␣-demethylase (14-DM) in the ergosterol biosynthesis pathway (4). The consequent ergosterol depletion affects cell membrane integrity and function and is believed to inhibit fungal cell growth and affect morphology.Efinaconazole, a novel triazole antifungal drug currently under development as a topical treatment for onychomycosis, has demonstrated efficacy in patients with toenail onychomycosis in two phase 3 clinical trials (5). Onychomycosis and other superficial mycoses are caused mainly by dermatophytes (e.g., Trichophyton rubrum and Trichophyton mentagrophytes) and yeast (e.g., Candida albicans). Efinaconazole possesses similar or higher antifungal activity against T. rubrum and T. mentagrophytes (MIC range, 0.00098 to 0.031 g/ml) and a broader spectrum of activity than those of currently marketed antifungals used in onychomycosis (6). We investigated the effects of efinaconazole on fungal ergosterol biosynthesis and dermatophyte hyphal morphology.In the present study, T. mentagrophytes strain SM-110 and C. albicans strain ATCC 10231 were used. The MICs of efinaconazole (Kaken Pharmaceutical), itraconazole, and clotrimazole (SigmaAldrich) were determined by the broth microdilution method using morpholinepropanesulfonic acid (MOPS)-buffered RPMI 1640, as described in CLSI documents M38-A2 (7) and M27-A3 (8), using visual endpoint readings of 80% growth inhibition at 4 days and 50% growth inhibition at 48 h, respectively. Efinaconazole was 4-fold more active than itraconazole against T. mentagrophytes SM-110 (MICs of 0.0039 and 0.016 g/ml, respectively). Similarly, efinaconazole was 8-fold more active than clotrimazole against C. albicans ATCC 10231 (MICs of 0.00098 and 0.0078 g/ml, respectively). The two strains showed typical susceptibilities to the antifungals tested, consistent with previous findings for these species (6, 9).Ergosterol biosynthesis assays were conducted by modifying the methods of Vanden Bossche et al. (10) and Ryder et al. (11). T. mentagrophytes (2 ϫ 10 8 microconidia/ml...

To provide an adequate therapeutic effect against onychomycosis, it has been suggested that topical drugs should have two properties: drug permeability through the nail plate and into the nail bed, and retention of their antifungal activity in the disease-affected areas. Only recently has the importance of other delivery routes (such as subungual) been discussed. Efinaconazole has been shown to have a more potent antifungal activity in vitro than the most commonly used onychomycosis treatments. The low keratin affinity of efinaconazole contributes to its effective delivery through the nail plate and retention of its antifungal activity. Its unique low surface tension formulation provides good wetting properties affording drug delivery both through and under the nail. High antifungal drug concentrations have been demonstrated in the nail of onychomycosis patients, and effectiveness of efinaconazole topical solution, 10% confirmed in two large well-controlled multicenter Phase 3 clinical studies in patients with mild-to-moderate disease.