J. Fungi 2015, 1, 107-114; doi:10.3390/jof1020107
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`OPEN ACCESS
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`
`
`Journal of Fungi
`ISSN 2309-608X
`www.mdpi.com/journal/jof
`
`Review
`Efinaconazole Topical Solution, 10%: Factors Contributing to
`Onychomycosis Success
`
`Richard A. Pollak 1,*, William J. Jo Siu 2, Yoshiyuki Tatsumi 3 and Radhakrishnan Pillai 2
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`1 San Antonio Podiatry Associates, San Antonio, TX 78229, USA
`2 Dow Pharmaceutical Sciences, a Division of Valeant Pharmaceuticals North America LLC,
`Petaluma, CA 94954, USA; E-Mails: wjo@dowpharmsci.com (W.J.J.S.);
`RPillai@dowpharmsci.com (R.P.)
`3 Kaken Pharmaceutical Co. Ltd., Kyoto 607-8042, Japan; E-Mail: tatsumi_yoshiyuki@kaken.co.jp
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`* Author to whom correspondence should be addressed; E-Mail: drrichardpollak@gmail.com;
`Tel.: +1-210-692-0279.
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`Academic Editor: Theodore Rosen
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`Received: 1 June 2015 / Accepted: 24 June 2015 / Published: 3 July 2015
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`Abstract: 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.
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`Keywords: onychomycosis; efinaconazole; topical therapy; fungi; toenail
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`1. Introduction
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`108
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`Onychomycosis is a progressive, common fungal infection of the nail bed, matrix or nail plate [1,2].
`It is difficult to treat successfully and can be extremely recalcitrant. The disease may be managed with
`oral or topical medication, with topical agents having low risk of hepatotoxic side effects and the
`drug-drug interactions usually associated with some systemic antifungals, such as itraconazole.
`Traditional formulation approaches to topical onychomycosis therapy have employed lacquers (i.e.,
`ciclopirox and amorolfine). These are organic solutions of film forming polymers. Upon application to
`the surface of the nail, the solvent evaporates, leaving a water resistant polymer film on the nail plate.
`This occlusive film acts as a reservoir from which drug is released, penetrating into and through the nail.
`One of the disadvantages of lacquers is that the film must then be removed, either mechanically or with
`organic solvents, and fresh lacquer applied to replenish this drug depot [3]; a process that can render the
`nail more prone to infection [4]. Indeed, ciclopirox lacquer required weekly removal of the product and
`it was also strongly recommended that patients see a podiatrist or their physician every few months for
`mechanical debridement of their toenails. However, the main concern with lacquer formulations is that
`efficacy in treating onychomycosis has been disappointing [5]. One reason for their low cure rates is
`thought to be the inability of drug to efficiently penetrate the nail plate [6–8].
`The intrinsic properties of a drug molecule and the vehicle in which the drug is formulated are both
`felt to be important contributors to topical treatment success in onychomycosis. Not only must an
`adequate amount of drug be delivered to the infection, its antifungal activity must be maintained within
`the keratin-rich environment of the nail. Both penetration through the nail and resultant drug activity can
`be restricted or decreased through keratin binding [9–11].
`The onychomycotic nail is visually very different to the healthy nail. Although these nails tend to be
`thicker [12,13], nail density and tensile strength are reduced, suggesting a more porous structure and
`erosion of the intracellular matrix, rendering the tissue more permeable to topically applied agents
`formulated in an aqueous vehicle solution [14]. Newer topical agents for onychomycosis (i.e.,
`efinaconazole and tavaborole) have been formulated as solutions. Complete cure rates of efinaconazole
`of 15.2% and 17.8% have been reported from two large Phase 3 clinical trials in mild to moderate
`onychomycosis [15].
`While much has been written about the topical treatment of onychomycosis and the challenge of
`effective nail penetration following product application to the nail surface, the potential of other delivery
`routes, such as subungual application at the hyponychium, has been largely overlooked. Efinaconazole
`topical solution, 10% is a uniquely formulated antifungal specifically developed for the treatment of
`toenail onychomycosis. Its formulation has both a low surface tension and good wetting properties [16],
`affording the potential of both transungual and subungual delivery of active drug to the infection.
`Our review highlights the in vitro and in vivo studies with efinaconazole, and presents data on
`transungual and subungual delivery to the site of infection in the nail bed, matrix, and nail plate in
`onychomycosis patients.
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`2. In Vitro Antifungal Activity of Efinaconazole
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`Most onychomycosis infections are due to dermatophyte fungi (mainly Trichophyton rubrum and
`Trichophyton mentagrophytes in about 80%–90% of cases) [17–20]; but can also be caused by
`nondermatophytes (mainly Scopulariopsis brevicaulis, although this can vary by country), and yeasts
`(mainly Candida albicans) [21]. Nondermatophyte infections are becoming increasingly prevalent in
`onychomycosis, either due to an artifact of improved diagnostic techniques or through increased
`awareness [22,23]. In addition, mixed infections have been reported, although their significance is less
`clear [24]. Therefore, an antifungal with a broad spectrum of activity is felt to be increasingly important
`in successfully treating onychomycosis [25].
`Efinaconazole has a broad antifungal activity against dermatophytes, nondermatophytes, and yeasts.
`Efinaconazole demonstrated antifungal activity against T. rubrum and T. mentagrophytes (MIC90:
`0.008–0.015 μg/mL) and C. albicans (MIC50: 0.004 μg/mL) and was more potent than the most
`commonly used antifungals in onychomycosis [26]. Against T. rubrum and T. mentagrophytes,
`efinaconazole had comparable activity (1 to 4-fold) to both amorolfine and terbinafine, and higher
`activity (8 to 64-fold) than ciclopirox and itraconazole [26]. Efinaconazole was significantly more potent
`(p < 0.001) in inhibiting C. albicans than terbinafine, ciclopirox, itraconazole and amorolfine [26].
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`3. Keratin Affinity and Transungual Penetration in Vitro
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`The upper (dorsal) layer of the nail is only a few cell layers thick but consists of hard keratin, and is
`the main barrier for drug permeation into and through the nail plate [27]. Many antifungal drugs are
`known to possess high keratin affinity, a property that may have a deleterious effect on their nail
`penetration and efficacy [28]. Keratin-bound drug does not contribute to the concentration gradient that
`would otherwise increase drug penetration, resulting in accumulation on the surface layers of the nail,
`decreased penetration into the deeper layers and the nail bed, and reduced antifungal activity [29].
`Terbinafine, for example, is 98.9% keratin-bound in vitro [28] and clinical trials through Novartis with
`a topical formulation have demonstrated poor efficacy results in onychomycosis despite its high
`in vitro antifungal activity [30]. When ciclopirox was applied to the nail for 14 days, penetration into the
`ventral side of the nail was 2 to 4 orders of magnitude lower than on the dorsal side [31].
`Efinaconazole has relatively lower binding to keratin, and faster release of bound drug from keratin
`when compared to ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin
`suspensions was 14.3% ± 0.4%, significantly higher than those seen with ciclopirox or amorolfine
`(0.7% ± 0.0%, and 1.9% ± 0.2%, respectively, p < 0.001) [28].
`The low keratin affinity of efinaconazole contributes to its favorable nail penetration [28]. In vitro
`nail permeation of efinaconazole was much greater than that seen with ciclopirox following a single
`application to human nails, whereas amorolfine levels were not detectable [28]. The cumulative
`permeated amounts of efinaconazole were 2.94 ± 3.91 μg/cm2 and 6.53 ± 8.15 μg/cm2 (mean ± SD),
`respectively at day 7 and 14; compared with 0.326 ± 0.590 μg/cm2 and 4.57 ± 6.89 μg/cm2 (mean ± SD),
`respectively for ciclopirox [28].
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`4. Transungual Penetration in Onychomycosis Patients
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`Onychomycosis patients were treated with efinaconazole topical solution, 10% for 28 days, with a
`follow-up at two weeks after the last drug application. Drug concentrations in the toenail (5.9 ± 5.1,
`6.0 ± 3.9, and 3.1 ± 3.2 mg/g at weeks 2, 4 and 6, respectively) were four orders of magnitude higher
`than MIC values of efinaconazole against T. rubrum and T. mentagrophytes. Concentrations of
`efinaconazole in the nail were not influenced by the presence of disease or nail thickness, and were
`maintained at high levels post-treatment (week 6) suggesting that the nail plate and nail bed continue to
`be exposed to inhibitory drug concentration for a period of time after treatment has ceased [32].
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`5. Subungual Penetration in Onychomycosis Patients
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`One possible explanation of the favorable clinical efficacy seen with efinaconazole topical solution,
`10% is that it may not rely solely on transungual delivery to the site of infection. The unique formulation
`provides low surface tension and good wetting properties [16]. As a result, as well as penetrating through
`the nail plate, the formulation spreads along the sides of the nail, under the cuticle, and through the
`hyponychium, enhancing drug delivery into the nail unit.
`In a study of 11 onychomycosis patients, vehicle solution was applied solely to the hyponychium and
`was shown to spread into the subungual space between the nail plate and nail bed, reaching the site of
`infection [33] (Figure 1).
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`Figure 1. Baseline (natural light) and post clipping (UV light) photographs of three
`representative patients. Subject 005: 55% nail involvement; subject 011: 35% nail
`involvement; subject 014: 40% nail involvement. In all subjects efinaconazole vehicle solution
`was applied to the hyponychium only. See [33] for detailed methodology and results.
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`6. In Vitro Antifungal Activity under the Nail Plate
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`111
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`The antifungal activity of efinaconazole solution (and ciclopirox and amorolfine nail lacquers) against
`T. rubrum in the underlying nail plate of isolated healthy human nails was evaluated in vitro to determine
`whether the drug penetrates across the nail plate and exerts an antifungal effect on dermatophytes under
`the nail plate [28]. Single application of efinaconazole to the surface of toenails inhibited the growth of
`T. rubrum. The lack of growth inhibition with the comparator lacquers may be due to the poor nail
`penetration of amorolfine (despite its high antifungal activity), and low antifungal activity of ciclopirox
`nail lacquer (despite adequate nail penetration) [28].
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`7. In Vitro Antifungal Activity in the Presence of Keratin
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`The in vitro onychomycosis model above (Section 6) evaluated the growth inhibitory effect of drug
`under the nail but not necessarily fungicidal activity. Thus, viable cell counts were further determined
`after incubation in keratin media, which has keratin as the sole energy nutrient and mimics the
`environment of the nail bed. The fungicidal activity of efinaconazole against T. mentagrophytes in
`keratin media was compared with ciclopirox and amorolfine to determine fungicidal potency inside the
`nail and in the nail bed. Efinaconazole showed fungicidal activity at a lower concentration than
`amorolfine and ciclopirox [28]. In addition, unlike amorolfine and terbinafine, which have higher keratin
`affinity, the growth inhibitory activity of efinaconazole was not affected by keratin [10]. These higher
`antifungal activities of efinaconazole in the presence of keratin may be reflective of its higher free
`(unbound) concentration relative to the comparator drugs. The relatively high antifungal activity of
`efinaconazole in the presence of keratin would lead to antifungal activity in the affected nail areas.
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`8. In Vivo Assessment of Efficacy in Guinea Pig Model of Onychomycosis
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`The comparative efficacy of efinaconazole topical solution, 10% was investigated in vivo in a
`refractory guinea pig onychomycosis model where nails were infected with T. mentagrophytes, and
`infection established over 4 weeks prior to treatment. The viable cell counts in nails treated with
`efinaconazole topical solution, 10% were significantly lower than those treated with ciclopirox
`and amorolfine nail lacquers (p < 0.01 and p < 0.001, respectively) following repeated treatment over
`four weeks [28].
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`9. Conclusions
`
`Onychomycosis is a very common fungal infection that can be difficult to treat successfully.
`To provide an adequate therapeutic effect, a topical antifungal must be able to reach the site of infection
`in sufficient concentration to eradicate the infecting pathogens. Efinaconazole is a broad spectrum
`antifungal with a higher in vitro potency than other agents frequently used to treat onychomycosis.
`Its low keratin affinity and unique formulation affords both transungual and subungual delivery to the
`site of infection in the nail bed, matrix and nail plate. Effective antifungal activity has been demonstrated
`experimentally in vitro and in vivo onychomycosis models, and high drug nail concentrations measured
`in onychomycosis patients that are well above antifungal concentrations. Clinical effectiveness of
`efinaconazole topical solution, 10% has been confirmed through two adequate and well-controlled large
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`multicenter studies in 1655 patients with mild to moderate onychomycosis [15] (Figure 2). The excellent
`therapeutic effects of efinaconazole may be attributable to the high nail penetration, potent antifungal
`activity under the nail plate, strong fungicidal activity in the presence of keratin, and a multi-directional
`delivery approach to treatment.
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`Figure 2. Baseline and study end (week 52) photographs of three representative patients.
`Subject 110–001: 25% nail involvement at baseline and 0% nail involvement at week 52;
`subject 111–025: 50% nail involvement at baseline and 10% nail involvement at week 52;
`subject 127–038: 45% nail involvement at baseline and 1% nail involvement at week 52.
`All subjects treated with efinaconazole topical solution, 10% daily for 48 weeks. See [15]
`for detailed methodology and results.
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`Acknowledgments
`
`The authors thank Brian Bulley, MSc (Inergy, West Sussex, UK) for assistance with the preparation
`of the manuscript. Valeant Pharmaceuticals, North America, LLC (Petaluma, CA, USA) funded Inergy’s
`activities pertaining to this manuscript.
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`Author Contributions
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`The authors contributed equally to this work.
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`Conflicts of Interest
`
`Pollak was an advisor to Valeant Pharmaceuticals and principal investigator in the efinaconazole
`phase 3 clinical programs. Jo Siu and Pillai are employees of Valeant Pharmaceuticals North America
`LLC. Tatsumi is an employee of Kaken Pharmaceutical Co. Ltd. (Kyoto, Japan).
`
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`© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
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