Curr Fungal Infect Rep (2016) 10:24–29
`DOI 10.1007/s12281-016-0250-9
`
`PHARMACOLOGY AND PHARMACODYNAMICS OF ANTIFUNGAL AGENTS (P GUBBINS, SECTION EDITOR)
`
`Antifungal Penetration into the Nail and New Topicals
`for Onychomycosis
`
`Lindsey M. Childs-Kean 1 & Jacqueline Jourjy 2
`
`Published online: 21 January 2016
`# Springer Science+Business Media New York 2016
`
`Abstract Onychomycosis is a common and difficult to treat
`infection, owing predominately to the limited penetration of
`topical drugs to the site of infection. Systemic drugs are not an
`option for all patients due to adverse events and drug-drug
`interactions. In this article, we review the nail penetration
`and clinical efficacy data of topical drugs, including older
`agents such as ciclopirox and amorolfine, as well as the newer
`agents, efinaconazole and tavaborole. Additionally, we
`describe some unresolved questions in the management of
`onychomycosis.
`
`Keywords Onychomycosis . Efinaconazole . Tavaborole .
`Ciclopirox . Amorolfine . Antifungal agents . Fungal
`infections
`
`Introduction
`
`Onychomycosis is defined as the fungal infection of the toe-
`nails or fingernails [1]. It is estimated that onychomycosis
`
`This article is part of Topical Collection on Pharmacology and
`Pharmacodynamics of Antifungal Agents
`
`* Lindsey M. Childs-Kean
`lchilds-kean@cop.ufl.edu
`
`Jacqueline Jourjy
`jjourjy@cop.ufl.edu
`
`1 Department of Pharmacotherapy and Translational Research,
`University of Florida College of Pharmacy, 9200 113th St N PH 102,
`Seminole, FL 33772, USA
`2 Department of Pharmacotherapy and Translational Research,
`University of Florida College of Pharmacy, 6550 Sanger Road,
`Orlando, FL 32827, USA
`
`accounts for 15–40 % of all nail infections, but true prevalence
`is difficult to estimate due to lack of large-scale epidemiolog-
`ical studies [1, 2]. Published guidelines recommend systemic
`treatment with terbinafine or itraconazole for most types of
`onychomycosis [1]. However, these antifungal agents are as-
`sociated with potentially serious drug-drug interactions and
`toxicities, such as hepatic dysfunction, which limit the patient
`populations who can receive them. Topical therapy has histor-
`ically not been effective because the nail plate is made of hard
`keratin and is hydrophilic, which limits penetration of lipo-
`philic and high molecular weight drugs. One study showed
`that the concentration of a topically applied drug decreased
`1000 times between outer layer and inner layer [3].
`Combination therapy with both systemic and topical therapy
`is an option in patients not likely to respond to topical mono-
`therapy [1]. This article will detail the nail penetration and
`monotherapy clinical data of two most commonly used his-
`torical topical treatments, amorolfine and ciclopirox, and that
`of two new topical therapies that have recently been approved,
`efinaconazole and tavaborole.
`
`Onychomycosis Trials Overview
`
`Most phase III trials for topical antifungal agents against
`onychomycosis have a non-drug-containing vehicle as its con-
`trol; there are few comparative trials of active antifungal
`agents. Unless otherwise specified in this review, the topical
`treatments were self-applied daily for 48 weeks. Additionally,
`unless otherwise noted, the primary outcome was complete
`cure, defined as a little to no (≤10 %) clinical involvement
`of the affected nail, plus mycologic cure, defined as a negative
`potassium hydroxide (KOH) preparation and negative fungal
`culture. Secondary outcomes included mycologic cure, clini-
`cal improvement, and assessment of adverse events. Table 1
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`Curr Fungal Infect Rep (2016) 10:24–29
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`25
`
`Table 1
`
`Efficacy rates of topical antifungals for onychomycosis
`
`Amorolfine 5 % nail lacquer
`compared to 2 % nail lacquer
`with nail filing and clipping [8]
`
`Ciclopirox 8 % nail lacquer
`compared to vehicle with nail
`filing and clipping [16]
`
`Efinaconazole 10 %
`solution compared to
`vehicle [26(cid:129)(cid:129), 27]
`
`Tavaborole 5 %
`solution compared
`to vehicle [33(cid:129)(cid:129)]
`
`Complete cure
`(clinical cure + mycologic cure)
`
`38 % vs. 12 %
`
`6.5 % vs. 0.9 % (study 1)
`12 % vs. 0.9 % (study 2)
`
`18.5 % vs. 4.7 %
`(pooled analysis)
`
`Mycologic cure
`
`60 % vs. 55 %
`
`29 % vs. 11 % (study 1)
`36 % vs. 9 % (study 2)
`
`55.2 % vs. 16.8 %
`(study 1) 53.4 % vs.
`16.9 % (study 2)
`
`6.5 % vs. 0.5 %
`(study 1) 9.1 % vs.
`1.5 % (study 2)
`31.3 % vs. 7.2 %
`(study 1) 35.9 % vs.
`12.2 % (study 2)
`
`shows the complete cure and mycologic cure rates for each
`drug in its respective late-stage clinical trials.
`
`Older Regimens
`
`Amorolfine
`
`Amorolfine is a morpholine derivative that exerts antifungal
`activity through inhibition of ergosterol synthesis at two levels
`in the fungal cell wall. This agent is active against dermato-
`phytes, yeasts, some molds, and other pathogenic fungi [4].
`Amorolfine is marketed throughout the world under various
`brand names for the topical nail treatment of onychomycosis.
`It is available in the form of a lacquer utilizing a water-
`insoluble transungual drug delivery system [5].
`Concentrations of amorolfine increase from 5 to 27 % after
`evaporation of lacquer solvents [6]. Polak et al. studied the
`pharmacokinetics of amorolfine in human nails and observed
`that amorolfine exceeded the minimum inhibitory concentra-
`tion (MIC) of most fungi causing onychomycosis as early as
`24 h after application [7].
`Lauharanta conducted a multicenter, randomized, double-
`blind, parallel design study to evaluate the efficacy and safety
`of amorolfine nail lacquer at two strengths—2 % vs. 5 %—
`applied once weekly [8]. Patients were randomly assigned to
`either the 2 % group or the 5 % group and were treated until
`complete cure or for 6 months. Study investigators assessed
`100 patients with onychomycosis for clinical response and
`mycologic findings. 38 % of patients in the 5 % amorolfine
`group experienced cure while 32 % experienced improvement
`and 30 % experienced failure. Only 12 % of patients in the 2 %
`group experienced cure (P = 0.008). Three months after stop-
`ping therapy, cultures were negative in 55 % of cases in the
`2 % group and 60 % of cases in the 5 % group. It is noteworthy
`that amorolfine nail lacquer is currently available in only the
`5 % formulation.
`An open-label, randomized, parallel-group study compared
`amorolfine 5 % nail lacquer applied once weekly versus twice
`weekly in patients with onychomycosis of the fingernails and/
`or toenails [9].Three hundred seventeen patients were
`
`included in the efficacy analyses. Assessment at 3 months
`after treatment completion showed the following results in
`the once weekly group: 45.6 % cure, 23.8 % improvement,
`and 30.6 % failure. In the twice weekly group, 51.8 % patients
`were cured while 21.7 % experienced improvement and
`26.5 % failed treatment. The investigators also determined
`that the clinical response to amorolfine treatment was time-
`dependent with greater than 50 % patients experiencing cure
`or improvement at 3 months after initiation of treatment.
`These numbers increased to 75 % in the once weekly group
`and 77.1 % in the twice weekly group at 3 months after the
`end of treatment. Of note, published guidelines recommend
`dosing amorolfine either once or twice weekly, despite no
`significant difference in efficacy between the dosing fre-
`quencies [1].
`
`Ciclopirox
`
`Ciclopirox is an 8 % topical solution in the form of a nail
`lacquer, which is approved by the Food and Drug
`Administration (FDA) for treatment of mild-to-moderate
`onychomycosis of fingernails and toenails without lunula in-
`volvement due to Trichophyton rubrum [10]. Ciclopirox has
`activity against the dermatophytes typically responsible for
`onychomycosis and is thought to act by chelating polyvalent
`cations, which inhibits the enzymes responsible for the break-
`down of fungal cell peroxides [10].
`The ciclopirox nail lacquer has been formulated to enhance
`penetration of the active drug through the nail plate thereby
`increasing its effectiveness. A newer formulation that contains
`a water-soluble polymer, hydroxypropyl chitosan, has greater
`affinity for keratin and may also be used to treat the area
`around the infected nail [11]. After evaporation of solvents
`contained in the lacquer, ciclopirox concentration reaches
`35 %, which provides a high concentration gradient for pene-
`tration into the nail [12]. One study of the standard 8 % nail
`lacquer formulation evaluated the in vitro penetration of
`ciclopirox in human fingernails and determined that the con-
`centrations of ciclopirox exceeded the MIC for common fun-
`gal pathogens [13].
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`Curr Fungal Infect Rep (2016) 10:24–29
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`A single center, randomized, open-label study compared
`the in vivo nail penetration of the water-soluble ciclopirox nail
`lacquer to a standard amorolfine lacquer and found that the
`water-soluble ciclopirox formulation had better nail penetra-
`tion at days 15 and 25 compared to the amorolfine lacquer that
`served as a reference [14(cid:129)]. Nail concentrations for ciclopirox
`were 2.82 ± 0.58 mcg/mg after 15 days and decreased by 34 %
`to 1.85 ± 0.31 mcg/mg on day 25 (P = 0.077). Nail concentra-
`tions for amorolfine were 0.64 ± 0.11 mcg/mg on day 15 and
`decreased by 80 % to 0.13 ± 0.03 mcg/mg on day 25
`(P = 0.0002). Both amorolfine concentrations were below the
`MIC for Candida parapsilosis and minimally exceeded the
`MIC for T. rubrum, the two pathogens studied in this analysis.
`Efficiency coefficients were calculated as ratios between the
`drug recovered in the nail and the MIC for T. rubrum and
`C. parapsilosis. Ciclopirox hydrolacquer showed significant
`superiority over amorolfine at both 15 days (P = 0.0008) and
`25 days (P < 0.0001) against C. parapsilosis and at 25 days
`against T. rubrum (P = 0.0008). Similar results were observed
`in a recent study by Monti et al. where the application of the
`ciclopirox hydrolacquer resulted in rapid nail penetration of
`the active drug and provided ciclopirox concentrations that
`sufficiently inhibited fungal growth for 7 days after the appli-
`cation [15(cid:129)].
`Gupta et al. conducted two identical double-blind, vehicle-
`controlled, parallel group, multicenter studies in the USA to
`evaluate the use of ciclopirox in adults with mild-to-moderate
`distal subungual tinea unguium of at least one great toenail with
`dermatophyte infection confirmed by both a positive KOH
`preparation and a positive dermatophyte culture [16]. Clinic
`evaluations occurred every 4 weeks. Drug application was on
`all toenails regardless of involvement and any affected finger-
`nails. Every 7 days, the patients removed the nail lacquer using
`isopropyl alcohol swabs. Secondary outcomes included
`treatment cure defined as simultaneous negative KOH and
`culture and a global evaluation score of Bcleared,^ mycologic
`cure, and negative mycologic culture.
`A total of 460 patients were randomized in the two studies,
`half received ciclopirox [16]. At 48 weeks (end of treatment),
`ciclopirox-treated patients had significant improvement com-
`pared to vehicle-treated patients. Treatment success was 6.5 %
`vs. 0.9 % (P = 0.031, study 1) and 12 % vs. 0.9 % (P = 0.001,
`study 2). Mycologic cure rates were higher in the ciclopirox
`group: 29 % versus 11 % (P = 0.002) and 36 % vs. 9 %
`(P < 0.001), in each study, respectively. Significant improve-
`ment in mycologic outcomes was seen as early as 12 weeks
`into the study period. Ciclopirox-treated patients also achieved
`a higher rate of treatment cure in both studies: 5.5 % vs. 0.9 %
`(P = 0.059, study 1) and 8.5 % vs. 0 % (P = 0.001, study 2).
`Patients who achieved treatment cure were eligible for an ad-
`ditional 12 weeks of follow-up. Seven out of 12 patients who
`were followed beyond 48 weeks remained cured while four of
`12 did not. The one remaining patient achieved negative
`
`mycology and was described to have nearly clear nails. Non-
`serious adverse events were reported in both ciclopirox and
`vehicle groups and included application site reactions, changes
`in nail shape or color, and localized erythema.
`Ciclopirox was studied in a multicenter, randomized, con-
`trolled trial comparing debridement alone every 3 months to
`debridement every 3 months plus ciclopirox daily for 9–12
`months as combination treatment for pedal onychomycosis
`[17]. Median follow-up time was 10.5 months. The primary
`outcome of this study was the presence or absence of fungi on
`final culture with or without positive fungal microscopy
`viewed with periodic acid-Schiff (PAS) staining. Seventy-
`seven percent of patients in the ciclopirox plus debridement
`group achieved mycologic cure compared to 0 % in the
`debridement only group.
`Another multicenter, prospective, randomized, controlled
`trial evaluated the efficacy and safety of a novel formulation
`of ciclopirox 8 % hydrolacquer (P-3051) compared to the
`marketed ciclopirox 8 % nail lacquer formulation in patients
`with mild-to-moderate distal subungual onychomycosis of at
`least one big toenail [18]. Patients were randomized to receive
`P-3051 (n = 182), the reference drug (n = 188), or placebo
`(n = 97). This treatment period was followed by a 4-week
`washout period and additional 8 weeks of follow-up.
`Efficacy variables of the target nail included KOH microscopy,
`fungal culture, and the percentage of infected nail area on the
`total nail surface. Complete cure after 48 weeks was signifi-
`cantly higher in patients who received P-3051 compared to
`placebo vehicle (5.7 % vs. 0 %, respectively, P = 0.0165) but
`not superior or significantly different when compared to the
`reference ciclopirox. At 60 weeks, the ciclopirox hydrolacquer
`(P-3051) group had 12.7 % complete cure, which was higher
`than the 5.8 % complete cure rate in the reference group
`(P < 0.05) and 1.3 % in the placebo group (P = 0.0029).
`
`New Regimens
`
`While the use of amorolfine and ciclopirox monotherapy may
`be effective for some patients, the efficacy rates are not opti-
`mal. Alternative dosing schemes of both agents have been
`tested without significant improvement [9, 19, 20].
`Additionally, other drugs, such as terbinafine, have been stud-
`ied as a topical formulation with limited efficacy [21].
`Therefore, additional new agents, ideally with enhanced nail
`penetration, have been sought for topical monotherapy.
`Recently, efinaconazole and tavaborole gained regulatory ap-
`proval for this indication.
`
`Efinaconazole
`
`Efinaconazole is a topical azole antifungal 10 % solution that
`works by inhibiting fungal lanosterol 14α-demethylase,
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`27
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`which prevents formation of ergosterol [22]. Efinaconazole
`has shown similar or increased potency against common
`onychomycosis-causing fungi, including T. rubrum,
`Trichophyton mentagrophytes, andCandida albicans , com-
`pared to other marketed onychomycosis treatments [23].
`Efinaconazole has been shown to have lower affinity to kera-
`tin than ciclopirox and amorolfine (P < 0.001 for each com-
`parison), leading to higher free drug concentrations [24(cid:129)].
`Additionally, efinaconazole produced a region of fungal
`growth inhibition under the nail in an in vitro study, where
`neither ciclopirox nor amorolfine did [24(cid:129)]. When tested in an
`in vivo guinea pig model, the viable fungal cell counts were
`significantly lower in those treated with efinaconazole than
`those treated with either ciclopirox or amorolfine (P < 0.01
`and P < 0.001, respectively) [24(cid:129)]. A separate analysis in a
`cadaver nail model indicated that efinaconazole’s nail pene-
`tration does not seem to be negatively impacted by the pres-
`ence of nail polish, unlike other topical products [25].
`The clinical efficacy of efinaconazole was evaluated in two
`identical phase III multicenter, randomized, parallel-group,
`double-blind, vehicle-controlled studies in patients with mild
`to moderate toenail onychomycosis [26(cid:129)(cid:129)]. Patients received
`either efinaconazole or vehicle without nail debridement with
`a 4-week intervention-free follow-up period. Efficacy and
`safety evaluations were completed at baseline, at 12-week
`intervals during treatment, and then at end of follow-up
`period.
`One thousand six hundred fifty-five patients were random-
`ized at 118 sites in the USA, Canada, and Japan [26(cid:129)(cid:129)]. The
`pooled study primary endpoint results showed significant dif-
`ferences in complete cure rates between efinaconazole and
`vehicle-treated patients (18.5 % vs. 4.7 %, P < 0.001), and
`the difference became statistically significant from week 36
`onwards [27]. Significant differences were also seen between
`efinaconazole and vehicle-treated patients for mycologic cure
`(55.2 % vs. 16.8 %, respectively, in study 1, 53.4 % vs.
`16.9 %, respectively, in study 2, P < 0.001 for both) and com-
`plete or almost complete cure (26.4 % vs. 7 %, respectively, in
`study 1, 23.4 % vs. 7.5 %, respectively, in study 2, P < 0.001
`for both) [26(cid:129)(cid:129)]. A subgroup analysis demonstrated that fe-
`males had higher complete cure rates than males (27.1 % vs.
`15.8 %, respectively, P = 0.001), and patients with mild dis-
`ease had higher complete cure rates than those with moderate
`disease (24.2 % vs. 14.5 %, respectively, P < 0.001) [27]. A
`post hoc analysis showed that patients in the phase III trials
`who had at least 10 % improvement in the affected nail by
`week 12 of treatment and those who had mycologic cure by
`week 24 were more likely to achieve complete cure [28]. In
`another post hoc analysis, patients in the phase III trials
`coinfected with tinea pedis had higher complete cure rates
`and mycologic cure rates when the tinea pedis was treated
`simultaneously compared to those in whom the tinea pedis
`was not treated simultaneously [29].
`
`Overall, efinaconazole adverse events were similar to ve-
`hicle (66 % vs. 61 %, respectively, in study 1, 64.5 % vs.
`58.5 %, respectively, in study 2) and generally mild or mod-
`erate in nature, not related to study drug, and resolved without
`complications. While the rate of discontinuation as a result of
`adverse events was higher for those receiving efinaconazole
`than vehicle (3.2 % vs. 0.5 %, respectively, in study 1, 1.9 %
`vs. 0 %, respectively, in study 2) and the most common ad-
`verse events leading to discontinuation were application site
`dermatitis and vesicles, other localized skin reactions were
`similar to vehicle [26(cid:129)(cid:129)].
`
`Tavaborole
`
`Tavaborole is a topical oxaborole antifungal 5 % solution with
`a novel mechanism of action of inhibiting an aminoacyl-
`transfer ribonucleic acid synthetase, thereby preventing fungal
`protein synthesis [30]. In vitro, tavaborole showed similar or
`lower minimum inhibitory concentrations (MICs) to a wide
`range of fungi, including T. rubrum, T. mentagrophytes, and
`C. albicans, when compared with ciclopirox, terbinafine, flu-
`conazole, and itraconazole [31(cid:129)]. Additionally, the MIC of
`T. rubrum to tavaborole was not significantly altered in the
`presence of keratin, indicating possible enhanced nail penetra-
`tion [31(cid:129)]. Tavaborole showed higher concentrations in the
`ventral/intermediate nail layer compared to ciclopirox after
`14 days of treatment (P = 0.003), and tavaborole nail penetra-
`tion was 40-fold greater than that of ciclopirox after 14 days of
`treatment (P < 0.004) [31(cid:129)]. Tavaborole also produced a region
`of fungal growth inhibition under the nail in an ex vivo study,
`where neither ciclopirox nor amorolfine did [31(cid:129)]. A separate
`ex vivo analysis indicated that tavaborole’s nail penetration
`does not seem to be negatively impacted by the presence of
`nail polish [32].
`The clinical efficacy of tavaborole was studied in two iden-
`tical phase III, multicenter, randomized, double-blind, paral-
`lel-group, vehicle-controlled trials in patients with mild to
`moderate toenail onychomycosis [33(cid:129)(cid:129)]. Patients received ei-
`ther tavaborole or vehicle without nail debridement with a 4-
`week treatment-free follow-up period. Efficacy and safety
`evaluations were made at baseline, week 2, week 6, and every
`6 weeks thereafter. The primary efficacy outcome was com-
`plete cure at week 52. Secondary efficacy endpoints included
`completely or almost clear affected nail, negative mycology,
`and completely or almost clear nail plus negative mycology.
`Completely clear nail was defined as no clinical evidence of
`onychomycosis, no onycholysis, and no subungual hyperker-
`atosis. Almost clear nail was defined as no more than minimal
`evidence of onychomycosis (≤10 % toenail plate that was
`dystrophic or discolored) with minimal onycholysis and
`subungual hyperkeratosis.
`One thousand one hundred ninety-eight patients were
`randomized at 59 sites in the USA, Canada, and Mexico
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`[33(cid:129)(cid:129)]. Patients who received tavaborole had a significantly
`higher complete cure rate than those receiving vehicle
`(6.5 % vs. 0.5 %, respectively, in study 1, P = 0.001;
`9.1 % vs. 1.5 %, respectively, in study 2, P < 0.001).
`Significant differences were also seen in completely or
`almost clear nail at week 52 (26.1 % vs. 9.3 %, respective-
`ly, in study 1, 27.5 % vs. 14.6 %, respectively, in study 2;
`P < 0.001 for both) and negative mycology (31.3 % vs.
`7.2 %, respectively, in study 1, 35.9 % vs. 12.2 %, respec-
`tively, in study 2; P < 0.001 for both).
`Overall, tavaborole treatment-emergent adverse events
`were similar to vehicle (64.4 % vs. 69.9 %, respectively, in
`study 1, 57.5 % vs. 54 %, respectively, in study 2), generally
`mild or moderate in nature, and not related or unlikely related
`to study drug [33(cid:129)(cid:129)]. Treatment-related treatment-emergent
`adverse events were more common with tavaborole than ve-
`hicle (8.8 % vs. 2.6 %, respectively, in study 1, 3.3 % vs.
`0.5 %, respectively, in study 2), mostly due to application site
`reactions. The most common treatment-related application site
`adverse events were exfoliation (2.7 %), erythema (1.6 %),
`and dermatitis (1.3 %). Rates of discontinuation due to ad-
`verse events were similar regardless of treatment group
`(0.3—1 %).
`
`Conclusions
`
`One of the biggest challenges for onychomycosis treat-
`ment
`is reaching the site of infection. In vitro,
`efinaconazole and tavaborole appear to penetrate the toe-
`nail plate better than other topical treatment options.
`While efinaconazole and tavaborole are attractive addi-
`tions to the onychomycosis armamentarium, complete
`cure and mycologic cure rates are still not optimal with
`these agents, with less than 20 % of patients in phase III
`trials achieving complete cure. Some additional questions
`remain with the use of efinaconazole and tavaborole, in-
`cluding if they can be used in patients with severe disease,
`as this is a patient population excluded from the phase III
`trials. The phase III studies only looked at 48-week treat-
`ment durations with a 4-week follow-up period, so the
`impact of longer treatment durations on outcomes, safety,
`and resistance, as well as the outcomes at time points after
`follow-up ended remain unknown. The question of wheth-
`er combining one of these topical agents with debridement
`or systemic therapy would improve outcomes is yet to be
`answered. Further studies will be required to answer these
`clinically important questions. Finally, further drug dis-
`covery trials are needed to determine if there are addition-
`al antifungal agents, systemic or topical, which would pro-
`vide higher rates of complete and mycologic cure without
`significant adverse events or drug-drug interactions for
`this complicated to treat disease.
`
`Compliance With Ethical Standards
`
`Conflict of Interest The authors declare that they have no competing
`interests.
`
`Human and Animal Rights and Informed Consent This article does
`not contain any studies with human or animal subjects performed by any
`of the authors.
`
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`
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`(cid:129) Of importance
`(cid:129)(cid:129) Of major importance
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