efinaconazole and Onychomycosis

Onychomycosis is a fungal nail infection that causes nail discoloration, nail plate thickening, and onycholysis. Efinaconazole 10% topical solution is an FDA-approved treatment for onychomycosis patients aged 6 years and above. The drug functions as an antifungal by disrupting ergosterol synthesis in the fungal cell membrane. It exhibits higher in vitro activity against dermatophytes than other available antifungals such as ciclopirox and itraconazole, and the activity is comparable to amorolfine and terbinafine. Efinaconazole also provides enhanced nail penetration compared with other topical antifungals due to low surface tension, poor water solubility, and low keratin affinity. The pharmacokinetic studies suggest that the efinaconazole topical delivery to the nail bed is not markedly affected by the presence of disease. There is a subset of onychomycosis patients who are more likely to respond to efinaconazole 10% solution: female patients, those with lower BMI, mild onychomycosis, a short disease duration, no infected non-target toenails (large toenail disease only), and when concomitant tinea pedis is treated. Experts recommend efinaconazole 10% topical solution as the first line for mild-to-moderate onychomycosis, pediatric onychomycosis, those with liver or kidney disease, and as maintenance therapy to prevent relapse. The side effects of topical efinaconazole are minimal: most commonly ingrown toenails, dermatitis, vesicles, and pain at the application site. Altogether, phase I and phase III clinical trials, and post-hoc analyses indicate that efinaconazole 10% topical solution is a safe and effective treatment for adult and pediatric onychomycosis, with a satisfactory mycological and clinical cure.

Topics: Administration, Topical; Adult; Antifungal Agents; Child; Female; Humans; Onychomycosis; Triazoles

Onychomycosis, a common nail disorder caused by fungal infection, can be managed pharmaceutically with oral or topical treatments. While oral treatments are often used first-line to treat nail infections, these systemic antifungals are not appropriate for all patients, and no oral treatments are approved for use in children in the USA. Given this need, topical antifungals were developed, which can be used as monotherapy or in combination with oral drugs.. Efinaconazole 10% solution is an azole antifungal indicated for topical treatment of toenail onychomycosis in pediatric and adult patients. This qualitative literature review summarizes available chemical, pharmacological, efficacy, safety, and post-marketing surveillance data of efinaconazole 10% topical solution. Efinaconazole 10% has been shown to be safe and efficacious regardless of disease severity/duration at baseline; patient gender, ethnicity, or age (including pediatrics); or comorbidities such as diabetes or tinea pedis. Overall, efinaconazole is a safe and effective clinical option for the treatment and management of onychomycosis.. Efinaconazole is the first new antifungal approved for onychomycosis in 10 years in the USA. It has comparable efficacy to systemic antifungal agents such as itraconazole, and a favorable adverse events profile with minimal systemic exposure and no drug-drug interactions.

Topics: Administration, Topical; Adult; Antifungal Agents; Child; Humans; Onychomycosis; Pediatrics; Triazoles

Successful management of onychomycosis is a challenge because cure rates with most antifungals are relatively low and recurrence rates are high. A drug-based approach by treating the nail alone may not suffice. There are several host-related factors (age, sex, body mass index [BMI], and patient's quality of life), disease-related factors (disease severity, duration, and the number of toenails affected), and comorbidities (tinea pedis and diabetes) that may affect treatment efficacy. Here, we review the post hoc analyses of the phase III trials of efinaconazole 10% solution that have investigated the impact of these factors on topical therapy for toenail onychomycosis. The significant clinical variables that may affect the efficacy of efinaconazole include sex, BMI, disease severity, disease duration, and tinea pedis. As older patients may have slower toenail growth and more severe, longstanding disease compared with younger patients, they may require longer treatment duration, beyond the 48-week standard regimen. Treatment compliance may need to be discussed for an improved health outcome. Therefore, these prognostic factors need to be carefully evaluated, which may aid in formulating individualized therapy to maximize treatment success.

Topics: Administration, Topical; Antifungal Agents; Foot Dermatoses; Humans; Nails; Onychomycosis; Quality of Life; Treatment Outcome; Triazoles

Onychomycosis was first described in the mid-1800's, and early treatment regimens involved applying corrosive substances and nail plate avulsion. It was not until the mid-1900's that more specific antifungal agents were utilized. Initially, only oral drugs were used, with ciclopirox 8% solution later approved in 1999. Presently, terbinafine, itraconazole, and fluconazole (off-label) are used for systemic onychomycosis therapy in the US, and topicals include ciclopirox, efinaconazole and tavaborole. Devices, topicals with new mechanisms of action, and oral medications with potentially better efficacy are now being explored for treatment of onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Humans; Itraconazole; Nail Diseases; Onychomycosis; Terbinafine; Triazoles

Tinea pedis and tinea unguium are the most common dermatophytoses seen in the daily practice of dermatology. According to a report in Japan Foot Week 2006, it is estimated that about 1 in 5 Japanese have tinea pedis and that about 1 in 10 have tinea unguium. Thus far, use of oral antifungal agents has been the first-line therapy for onychomycosis. Many patients with onychomycosis, however, are elderly and have concomitant diseases as well as liver function disorder. Moreover, oral medications are reportedly associated with risks of impaired liver function and interactions. Due to such risks, therefore, treatment with topical agents is the only applicable therapy for most patients with onychomycosis. Recently, two topical agents (efinaconazole in 2014 and luliconazole in 2016) have been approved for the treatment of onychomycosis in Japan. Efinaconazole 10% solution is a triazole antifungal drug developed in Japan. Due to its low keratin affinity, efinaconazole shows high transungual penetration into nails and retains a high antifungal activity in the nail plate and the nail bed. Luliconazole 5% solution is an imidazole antifungal agent that has high keratin affinity. Luliconazole has also been shown in vitro to permeate from the superficial to the deep layers of the nail and to achieve concentrations above the MIC in all layers of the nail. Both efinaconazole 10% solution and luliconazole 5% solution have high antifungal activities for Trichophyton species. These two topical agents, therefore, have certainly increased treatment options for onychomycosis in the daily practice of dermatology.

Topics: Administration, Topical; Antifungal Agents; Drug Resistance, Fungal; Humans; Imidazoles; Keratins; Nails; Onychomycosis; Solutions; Triazoles; Trichophyton

Onychomycosis is a fungal nail infection caused by dermatophytes, nondermatophytes, and yeast, and is the most common nail disorder seen in clinical practice. It is an important problem because it may cause local pain, paresthesias, difficulties performing activities of daily living, and impair social interactions. The epidemiology, risk factors, and clinical presentation and diagnosis of onychomycosis were discussed in the first article in this continuing medical education series. In this article, we review the prognosis and response to onychomycosis treatment, medications for onychomycosis that have been approved by the US Food and Drug Administration, and off-label therapies and devices. Methods to prevent onychomycosis recurrences and emerging therapies are also described.

Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Fluconazole; Humans; Itraconazole; Laser Therapy; Nanoparticles; Onychomycosis; Photochemotherapy; Plasma Gases; Prognosis; Pulse Therapy, Drug; Risk Factors; Secondary Prevention; Severity of Illness Index; Terbinafine; Triazoles

The purpose of this article is to review the safety, efficacy, and role of efinaconazole and tavaborole in the treatment of onychomycosis.. Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, and nondermatophyte fungi. Distal and lateral subungual onychomycosis (DLSO) accounts for the majority of the cases. These infections cause structural damage to the nail which makes treatment difficult. Both oral and topical agents exist for the treatment of onychomycosis. Oral medications have generally been more effective, yet adverse effects and drug interactions limit their use in some patients. Food and Drug Administration (FDA)-approved agents in the United States for oral therapies include terbinafine, itraconazole, and griseofulvin. The only topical product available up to recently was ciclopirox.. This article will review efinaconazole and tavaborole, 2 new topical antifungal agents released in 2014.

Topics: Administration, Topical; Animals; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Foot Dermatoses; Humans; Microbial Sensitivity Tests; Onychomycosis; Triazoles

The patient was a 73-year-old healthy female farmer who had been treated with terbinafine for 25.5 months by a primary physician. She exhibited a discoloration and thickening of the right big toenail. She had no concomitant paronychia. Direct microscopy revealed chlamydoconidia and hyphae, and periodic acid-Schiff stained nail specimen showed septate hyphae. On the basis of these morphological features and gene analysis, the final diagnosis was ungual hyalohyphomycosis caused by Fusarium proliferatum. Topical application of 10% efinaconazole solution cured the disease in 10 months.

Topics: Administration, Topical; Aged; Antifungal Agents; Female; Foot Dermatoses; Fusariosis; Fusarium; Humans; Hyphae; Naphthalenes; Onychomycosis; Terbinafine; Triazoles

Onychomycosis is a common and difficult-to-treat fungal infection of the nail unit that gradually leads to dystrophic changes of the nail plate and nail bed. If untreated, infection progresses and may lead to discomfort, reduced quality of life, and risk of complications in patients with comorbid conditions (eg, diabetes, human immunodeficiency virus, peripheral vascular disease). Onychomycosis treatments are designed to eradicate causative pathogens (most commonly Trichophyton rubrum and Trichophyton mentagrophytes), restore healthy nails, and prevent recurrence or spread of infection. Given the deep-seated nature of most cases of onychomycosis, an effective antifungal agent needs to achieve and maintain sufficient drug concentrations throughout the nail unit for the duration of healthy nail in-growth. Oral antifungal drugs are the most effective available therapy and are generally well tolerated, but may be limited by safety concerns and the potential for drug-drug interactions (DDIs). Thus, treating physicians and pharmacists must be cognizant of a patient's current medications; indeed, it may not be feasible to treat onychomycosis in patients with diabetes, heart disease, or depression because of the risk for DDIs. Current topical therapy is not associated with risk of DDIs. Tavaborole and efinaconazole, two recently approved topical agents, have demonstrated good nail penetration and high negative culture rates in clinical trials of patients with onychomycosis. This article provides the treating physician and pharmacist with information on the safety and effectiveness of current oral (allylamine, azole) and topical (ciclopirox, efinaconazole, tavaborole) treatment to aid in making informed treatment decisions based on the unique characteristics (medication history, comorbidities, nature of onychomycosis) of each patient.

Topics: Administration, Oral; Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chemical and Drug Induced Liver Injury; Ciclopirox; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Itraconazole; Naphthalenes; Onychomycosis; Pyridones; Terbinafine; Triazoles

Onychomycosis is an often overlooked and/or undertreated disease. This may be in part due to an under appreciation among both physicians and patients of its impact on quality of life and the potential for significant complications, from tinea corporis and cruris, to bacterial superinfection. Some health care providers are unaware of the effective low-risk treatments currently available. Changing demographic characteristics such as the relative aging of the population; the increasing prevalence of diabetes and peripheral vascular disease, and widespread iatrogenic immunosuppression; and changes in lifestyle practices such as earlier and greater participation in sports, are likely to lead to an increased prevalence of onychomycosis in both adults and children. Two topical onychomycosis treatments, efinaconazole 10% solution, and tavaborole 5% solution were recently approved by the FDA. This article reviews the state of knowledge and describes, briefly, these new treatment options.

Topics: Anti-Infective Agents, Local; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Onychomycosis; Pharmaceutical Solutions; Treatment Outcome; Triazoles

Topics: Animals; Antifungal Agents; Clinical Trials as Topic; Drug Resistance; Humans; Onychomycosis; Pharmaceutical Solutions; Triazoles

Efinaconazole 10% topical solution is a new antifungal therapy for the topical treatment of mild to moderate toenail onychomycosis. In vitro and in vivo data have shown significant antifungal activity against dermatophytes, Candida spp. and nondermatophyte molds, and its mechanism of action is through inhibition of fungal lanosterol 14α-demethylase. In two parallel, double-blind, randomized, controlled, Phase III trials, complete cure rates were 17.8 and 15.2%, respectively, and mycological cure rates were 55.2 and 53.4%, respectively, for efinaconazole 10% topical solution, which were superior to vehicle, with minimal adverse events. This drug profile reviews the most recent basic science and clinical data for efinaconazole in the treatment of toenail onychomycosis.

Topics: Administration, Topical; Animals; Antifungal Agents; Foot Dermatoses; Humans; Onychomycosis; Triazoles

Although there are limited data available on gender as an outcome variable in the treatment of onychomycosis, differences in disease prevalence and impact in males versus females have been observed. This article provides a gender subgroup analysis based on results from recent studies evaluating the efficacy, safety, and tolerability of efinaconazole topical solution 10% in the treatment of onychomycosis. Data were collected from two 52-week, prospective, multicenter, randomized, double-blind studies of patients 
(age range, 18-70 years) randomized to receive either efinaconazole topical solution 10% or vehicle for treatment of onychomycosis. Results from this analysis indicated that once-daily application of efinaconazole topical solution 10% may provide a useful topical option for treatment of mild to moderate toenail onychomycosis, especially in female patients.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Prospective Studies; Randomized Controlled Trials as Topic; Sex Factors; Treatment Outcome; Triazoles; Young Adult

Approximately 20-25% of the population worldwide is affected by superficial cutaneous mycoses (SCM). SCM are cutaneous fungal infections with a wide array of systemic and topical treatment options. However, successful therapeutic outcomes are limited by patient non-adherence, medication side effects, potential drug interactions, antifungal resistance and disease recurrence. Advances in formulation technology have allowed for the development of more effective and safer therapies. In this article we will review several new and emerging pharmacotherapeutics for onychomycosis and tinea pedis.

Topics: Allylamine; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Education, Medical, Continuing; Humans; Imidazoles; Itraconazole; Onychomycosis; Tinea Pedis; Triazoles

Onychomycosis is a fungal infection of the nail apparatus that can be challenging to treat due to the modest efficacy of existing antifungal therapies and a high rate of relapse and recurrence.. To investigate the efficacy and safety of efinaconazole 10% solution in pooled Phase III clinical trial participants with mild to moderate onychomycosis.. Phase III clinical trials data from NCT01008033 and NCT01007708 were pooled. Efficacy analysis for the primary and secondary outcome variables was conducted using the mITT population and analysed using Cochran-Mantel-Haenszel tests. Subgroup analysis was conducted for prognostic factors that may affect drug efficacy. Safety analysis was conducted on all recipients of a single drug dose.. Efinaconazole 10% nail solution was superior to vehicle for all primary and secondary outcome measures assessed. Complete cure was 18.5% vs 4.7% P< 0.001 [mITT] and mycological cure was 56.3% vs 16.6%, P< 0.001 [mITT]. Complete or almost complete cure and treatment success were achieved in 27.7% and 47.2% compared to 7.9% and 18.2% with vehicle, respectively (P< 0.001 [mITT]). In all subgroups, efinaconazole 10% solution had statistically higher cures rates compared to vehicle. Higher complete cure rates were observed in women and individuals with mild disease (≤33% involvement), but not in any other subgroup assessed. Treatment associated adverse events in the efinaconazole 10% solution group were similar to vehicle and limited to local site reactions (2%).. The findings from this pooled analysis suggest that efinaconazole 10% solution may become the preferred topical agent for mild to moderate onychomycosis.

Topics: Administration, Topical; Aged; Antifungal Agents; Clinical Trials, Phase III as Topic; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Pharmaceutical Solutions; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome; Triazoles

Toenail onychomycosis is a common disease with limited treatment options; treatment failure and relapse are frequently encountered. Many patients experience long-standing disease affecting multiple toenails, with substantial discomfort and pain. Although some patients might prefer a topical therapy, efficacy with ciclopirox nail lacquer has been disappointing.. Efinaconazole topical solution, 10% is the first topical triazole antifungal agent specifically developed for the treatment of onychomycosis. This paper reviews the preclinical and clinical data on efinaconazole topical solution, 10%.. Efinaconazole has a broad spectrum of antifungal activity in vitro and is more potent than ciclopirox against common onychomycosis pathogens. It has a more optimal keratin affinity than ciclopirox, and it exhibits significantly greater in vivo activity owing to its superior nail penetration. Mycologic cure rates at week 52 were 55.2% (study 1) and 53.4% (study 2) with efinaconazole topical solution, 10% compared with 16.8% and 16.9%, respectively, with vehicle (P<.001 for both). In addition, efinaconazole is well tolerated.. Efinaconazole topical solution, 10% may likely become a preferred topical agent for the management of mild-to-moderate onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Foot Dermatoses; Humans; Onychomycosis; Triazoles

Onychomycosis is a very common nail disorder seen in dermatological practice. It is difficult to treat successfully for a multitude of reasons, and although topical antifungal therapy might be considered ideal for mild to moderate onychomycosis, efficacy has been limited by poor nail penetration of active ingredient through the nail plate into the nail bed and nail matrix to the site of infection. The intrinsic properties of an antifungal and its vehicle formulation are both considered important contributors to effective treatment. Here we review the formulation approach to efinaconazole topical solution, 10% an effective and well-tolerated treatment for onychomycosis. We demonstrate that the low surface tension formulation affords better penetration of efinaconazole through the nail plate, and also to the site of infection by spreading into the space between the nail and nail bed.

Topics: Administration, Topical; Antifungal Agents; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Nails; Onychomycosis; Permeability; Triazoles

Topics: Administration, Cutaneous; Adolescent; Antifungal Agents; Child; Female; Foot Dermatoses; Humans; Male; Onychomycosis; Solutions; Treatment Outcome; Triazoles

Onychomycosis, a difficult-to-treat fungal nail infection, is more prevalent in the elderly. Efinaconazole 10% topical solution is a firstline therapy for onychomycosis, based on phase III trials of 12-month treatment; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. This is the first efficacy and safety data for a 24-month duration of efinaconazole 10% topical solution treatment for onychomycosis. Enrolled patients (N = 101) with mild to moderate distal lateral subungual onychomycosis applied efinaconazole to all affected toenails once daily for 18-24 months. Efficacy and safety were evaluated at months 6, 12, 18, and 24 (M6, M12, M18, and M24). The study is ongoing; to date, 47 patients have completed to M24. Mycological cure (MC) was 60.0% at M12, increasing to 74.2% at M24; effective cure (MC and ≤10% clinical involvement of the target toenail) was 17.8% at M12, rising to 19.4% at M24. Mild to moderate application site reactions were the only efinaconazole-related adverse events in 8 patients (7.9%). Increased age, increased severity of onychomycosis, and the presence of mixed infections (dermatophyte plus non-dermatophyte moulds) may drive a need for longer treatment durations. Although the data are interim, there is a trend of increasing efficacy beyond M12 use, without increased safety risk, even in patients >70 years of age.

Topics: Administration, Cutaneous; Aged; Antifungal Agents; Drug Administration Schedule; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Triazoles

Efinaconazole is non-lacquer-based with a low surface tension that efficiently targets delivery of active ingredient into the nail and nail bed.. To develop an optimal, stable formulation of efinaconazole topical solution 10% (ETS10).. We evaluated the safety and efficacy of ETS10 on 10 Iranian participants in a pilot, single-group and before-after clinical study, for up to 8 weeks in onychomycosis.. The study showed reasonable results concerning the short period of treatment. During the period of storage, the formulation showed no variation in colour, odour and pH. The average pH at initial, 1st, 6th and 12th months was 4.65, 4.64, 4.65 and 4.64, respectively. The assay of an active pharmaceutical ingredient in the formulation was desired over the whole period. This indicates that antimicrobial activity has been adequate and efficient. A significant decrease in Investigator Global Assessment (IGA) of the target toenails was also defined as the efficacy endpoint. The median score for IGA at baseline visit was 3 out of 5 which decreased to 2 out of 5 and the decrease was statistically significant.. The study clarifies the new efficacy of ETS10 in subjects with onychomycosis and passed the safety study successfully. These properties may develop the potentiality of ETS10 as a good treatment option for patients with onychomycosis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Female; Foot; Humans; Male; Middle Aged; Nail Diseases; Nails; Onychomycosis; Pilot Projects; Triazoles; Young Adult

Onychomycosis is especially common among diabetic patients. The purpose of this study was to investigate the efficacy of 10% efinaconazole solution among diabetic subjects, without restriction by nail plate involvement or glycemic control. Forty subjects were enrolled, with 36 reaching their final 50-week follow-up visit. Mycological cure was attained by 21 subjects (58.33%); 8 subjects (20%) attained either clinical cure (0% clinical involvement) or treatment success (≤10% clinical involvement). Glycemic control did not affect clinical outcome. The medication was well tolerated, with 4 local adverse events and no significant adverse events. The medication may represent a useful option for diabetic patients.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Blood Glucose; Diabetes Complications; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Triazoles

Onychomycosis is a difficult to treat condition whose prevalence is increasing. Until recently, there was no FDA approved antifungal agent for the treatment of onychomycosis in children. Although systemic antifungal agents are effective, their use is restricted by the potential adverse events and drug-drug interactions. There is evidence regarding the safety and efficacy of topical antifungal agents for pediatric onychomycosis. We have summarized the results of a recently published study using efinaconazole topical solution 10% to treat onychomycosis in children and discuss management of pediatric onychomycosis. In a multicenter, open-label phase 4 study, efinaconazole 10% solution was applied topically once daily in children aged 6 to 16 years with mild to severe, culture positive, distal and lateral subungual onychomycosis. Treatment was for 48 weeks with a follow-up at week 52. Pharmacokinetics was performed in a subset of patients. There were 62 patients enrolled in the study. At week 52, the efficacy was mycological cure rate 65% and complete cure rate 40%. All treatment-emergent adverse events (TEAE) were mild to moderate in severity with none resulting in study discontinuation. The only treatment-related TEAE was ingrown toenail. Efinaconazole was detected at low levels in plasma. Efinaconazole topical solution 10% is effective and safe in treating onychomycosis in children age 6 to 16 years and was recently FDA-approved for this indication. The on-label use of other topical agents, tavaborole solution 5% and ciclopirox nail lacquer solution 8% is reviewed. We also briefly discuss the use of oral agents, terbinafine, itraconazole, and fluconazole in pediatric onychomycosis.

Topics: Administration, Topical; Adolescent; Antifungal Agents; Child; Foot Dermatoses; Humans; Multicenter Studies as Topic; Onychomycosis; Triazoles

Pediatric onychomycosis management is challenging as there are limited treatment options. The objective of this study was to evaluate efinaconazole 10% topical solution in children with onychomycosis.. This phase 4, multicenter, open-label study (NCT02812771) evaluated safety, pharmacokinetics (PK), and efficacy of efinaconazole 10% topical solution in pediatric participants (6-16 years). Efinaconazole was administered once daily for 48 weeks, with a 4-week posttreatment follow up. Participants had culture-positive, mild-to-severe distal lateral subungual onychomycosis affecting at least 20% of at least 1 great toenail. The PK subset included participants 12-16 years with moderate-to-severe onychomycosis affecting at least 50% of each great toenail and onychomycosis in at least 4 additional toenails.. Of 62 enrolled participants, 60 were included in the safety population and 17 in the PK population. Efinaconazole 10% topical solution was well tolerated. The concentration-time profiles for efinaconazole and its major metabolite were relatively stable, with only minor fluctuations during the 24-hour dosing interval. Systemic exposure to efinaconazole was low. By week 52, 65.0% of participants achieved mycologic cure, with a 36.7% mycologic cure rate observed as early as week 12. A total of 40.0% of participants achieved complete cure, 50.0% achieved clinical efficacy, and 88.3% achieved fungal cure by week 52.. Efinaconazole was safe and efficacious in pediatric participants with mild-to-severe onychomycosis, with improved mycologic cure and complete cure rates compared with adults from two 52-week studies. J Drugs Dermatol. 2020;19(9):867-872. doi:10.36849/JDD.2020.5401.

Topics: Administration, Topical; Adolescent; Antifungal Agents; Area Under Curve; Child; Female; Follow-Up Studies; Foot Dermatoses; Fungi; Humans; Male; Onychomycosis; Severity of Illness Index; Solutions; Treatment Outcome; Triazoles

Onychomycosis is a common but difficult to treat nail disorder. Treatment strategies thus far have included oral and topical antifungals, surgical treatment and recently lasers have emerged as a therapeutic modality.. The objective of this study was to assess whether efinaconazole together with laser would result in greater clinical and mycologic cure and lower rate of relapse compared to efinaconazole alone.. Thirty subjects were randomized to either self-apply efinaconazole 10% once daily for 48 weeks, or follow the same treatment plan but also receive six treatments with a 1064 nm Nd: YAG laser every 4 weeks. The primary endpoint was to assess the proportion of subjects who achieved complete cure at week 52.. The combination therapy group showed significantly quicker mycological cure at the 48- and 52-week follow-up.. Both efinaconazole and combination with laser were efficacious treatment, but the combination therapy leads to quicker resolution with fewer rate of relapse.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Combined Modality Therapy; Female; Follow-Up Studies; Foot Dermatoses; Humans; Laser Therapy; Lasers, Solid-State; Male; Middle Aged; Onychomycosis; Patient Satisfaction; Photography; Statistics, Nonparametric; Treatment Outcome; Triazoles

We evaluated the efficacy of efinaconazole 10% topical solution in long-term use, for up to 72 weeks, for onychomycosis, including severe cases. Among 605 participants, 219 patients diagnosed as having onychomycosis were evaluated for the efficacy of efinaconazole. The treatment success rate (<10% clinical involvement of the target toenail) at the final assessment time point was 56.6%, the complete cure rate was 31.1% and the mycological cure rate was 61.6%, all of which increased over time, demonstrating that continuous application contributed to the improvement of cure rate. Even in severe cases, reduction of the affected nail area was observed, showing the potential efficacy of the treatment. Responses to a quality of life questionnaire among patients with onychomycosis, OnyCOE-t, suggested that efinaconazole treatment improved the patients' quality of life. The incidence of adverse drug reaction in the patients eligible for the assessment was 6.3%, and this developed only in the administration site in all cases. No systemic adverse event was observed. In addition, no increase in the incidence of adverse drug reaction due to long-term use was found. Efinaconazole therapy was proved to exhibit excellent balance between efficacy and safety, and thus may serve as a useful treatment option for onychomycosis.

Topics: Administration, Topical; Aged; Antifungal Agents; Drug-Related Side Effects and Adverse Reactions; Female; Foot Dermatoses; Humans; Incidence; Long-Term Care; Male; Middle Aged; Onychomycosis; Quality of Life; Severity of Illness Index; Time Factors; Treatment Outcome; Triazoles

Onychomycosis is a common disease that remains a difficult disorder to treat despite the introduction of new topical agents; and not all patients are cured. Clinical experience leads us to suggest a number of host-related factors can affect the chance of cure, but studies supporting these observations are currently lacking. Although many studies, particularly on topical agents, rely on severity classification when selecting patients for inclusion, a pilot study was unable to demonstrate any prognostic value of the extension of nail involvement. In addition, no universal severity classification exists, and most studies do not report prognostic factors.. To investigate the efficacy of efinaconazole topical solution, 10% in patients with mild-to-moderate onychomycosis and determine the impact of baseline severity on treatment outcome.. Post hoc pooled analysis of two identical, multicenter, randomized, double-blind, vehicle-controlled studies in 1655 patients aged 18-70 years with a clinical and mycological diagnosis of mild-to-moderate dermatophyte toenail onychomycosis (20-50% clinical involvement). Patients were randomized (3:1) to efinaconazole 10% solution or vehicle, once-daily for 48 weeks, with 4-week post treatment follow-up. Efficacy criteria included clear nail (0% target nail plate involvement), almost clear nail (≤5% target nail plate involvement), and clinical treatment success (≤10% target nail plate involvement) at week 52. For the post hoc analysis, patients were classified as mild (20%-29% nail involvement), moderate (30%-39%), and moderately severe (40%-50%) at baseline.. Overall, 25%, 23%, and 52% of patients had mild, moderate, or moderately severe disease at baseline. Baseline nail involvement did not appear to predict treatment outcomes. The proportion of patients with mild disease who had a clear nail progressively reduced by week 36 (58%) and week 48 (41%), and even further by week 52 (37%). Of the 237 patients treated with efinaconazole who were 'clear' at week 52, 37%, 24%, and 39% had mild, moderate or moderately severe disease respectively at baseline. The majority of patients (N=634) saw at least a 50% improvement in their target toenail by week 52. Almost half of these patients (N=312, 49.2%) were moderately severe at baseline.. This post hoc analysis supports previous data showing good efficacy of efinaconazole in mild onychomycosis. The relative contribution to overall efficacy results at week 52 of patients with moderate or moderately severe disease was unexpected for a topical therapy, and warrants further study, especially as they represent the majority of patients enrolled in the two studies. It is possible that comparable efficacy can be achieved in these more severe patients with longer treatment courses, or follow-up. J Drugs Dermatol. 2018;17(2):175-178.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Prognosis; Severity of Illness Index; Treatment Outcome; Triazoles; Young Adult

Onychomycosis is a common disease that remains difficult to treat despite the introduction of new topical agents. Clinical trials on efinaconazole and tavaborole included 48 weeks' daily treatment regimens with a 4-week follow-up. It has been suggested that either a longer treatment regimen or longer follow-up would lead to even better results, primarily due to the time taken for the diseased nail to grow out, especially in those patients with more severe disease.. To investigate the impact of a longer follow-up period on the efficacy of efinaconazole 10% topical solution in patients with moderate-to-severe onychomycosis.. &Single center, open-labeled study in 23 subjects aged 18-80 years with a clinical and mycological diagnosis of moderate-to-severe dermatophyte toenail onychomycosis (40-75% clinical involvement). Subjects were treated with efinaconazole 10% solution, once-daily for 48 weeks, with two 12-week post-treatment follow-ups (at week 60 and 72). Primary efficacy endpoint was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture). Secondary endpoints included mycologic cure rates and treatment success (defined as those patients who had at least a 50% improvement in affected toenail from baseline).. Twenty-two subjects completed the study. Mean baseline age 59.4 years (range, 37-77), predominance of male subjects (73.9%). Median baseline severity 50% affected target toenail. At week 72, two subjects were complete cures and 56.5% of subjects achieved treatment success. There were no complete cures at week 48, but 39.1% achieved treatment success. Mycologic cure rates were 91.3% at week 48. Median percent affected target toenail reduced to 40%, and further to 25% (week 48 and 72, respectively). Treatment was well tolerated, with no adverse events related to medication.. This single-center phase 4 study supports previous data showing good efficacy and tolerability of efinaconazole in moderately severe onychomycosis. Continued reduction in disease severity post-treatment suggest that a longer follow-up of patients treated with efinaconazole would afford better efficacy results, as indicated by greater treatment success, and increase in number of subjects who became complete cures.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Triazoles; Young Adult

Onychomycosis is the most common disease of the nail in adults. International guidelines urge health care professionals to perform confirmatory diagnostic testing before initiating systemic therapy. This approach was determined to be cost-effective in studies from the late 1990s but has not been evaluated more recently. The effect of testing on the costs of efinaconazole, 10%, topical solution treatment is unknown.. To evaluate the cost and potential harm associated with 3 approaches to onychomycosis evaluation before treatment with oral terbinafine or efinaconazole, 10%.. A decision analysis that compared the costs of 3 onychomycosis management algorithms based on recently published data of test statistics, disease prevalence, and relevant costs: (1) empirical therapy without confirmatory testing, (2) pretreatment confirmatory testing with potassium hydroxide (KOH) stain followed by periodic acid-Schiff (PAS) evaluation if KOH testing is negative, and (3) pretreatment testing with PAS. There was no direct patient evaluation. Selection of included studies was based on outcome variables and the quality of study design. The study was conducted from April 1, 2014, to September 1, 2015.. Primary outcomes included direct cost of onychomycosis testing and therapy and cost to avoid harm when treating patients with oral terbinafine.. At a disease prevalence of 75%, per-patient cost savings of empirical terbinafine therapy without confirmatory testing was $47 compared with the KOH screening model and $135 compared with PAS testing. The cost of testing necessary to prevent a single case of clinically relevant liver toxic effects related to terbinafine at a prevalence of 75% was between $18.2 million and $43.7 million for KOH screening and between $37.6 million and $90.2 million for PAS testing. At a prevalence of 75%, KOH screening and PAS testing before treatment with efinaconazole, 10%, saved $272 and $406 per patient per nail, respectively.. These results show that empirical treatment with terbinafine for patients with suspected onychomycosis is more cost-effective than confirmatory testing across all prevalence of disease, with minimal effect on patient safety. In contrast, confirmatory testing before treatment with efinaconazole, 10%, is associated with reduced costs. Blanket recommendations for confirmatory testing before systemic therapy should be reconsidered and replaced with recommendations tailored to specific therapies.

Topics: Administration, Oral; Administration, Topical; Algorithms; Cost Savings; Cost-Benefit Analysis; Decision Support Techniques; Decision Trees; Health Care Costs; Humans; Hydroxides; Naphthalenes; Onychomycosis; Periodic Acid-Schiff Reaction; Potassium Compounds; Potentially Inappropriate Medication List; Terbinafine; Triazoles

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Female; Follow-Up Studies; Foot Dermatoses; Humans; Male; Onychomycosis; Risk Assessment; Treatment Outcome; Triazoles

Although a completely normal nail would be the ideal outcome when treating onychomycosis, this is not always achievable and long treatment courses or patient expectations can impact patient adherence.. We analyzed cure rates from a number of subpopulations derived from the two pivotal phase III studies with efinaconazole topical solution (10%) to provide some insights into clinically meaningful treatment outcomes and support for effective long-term management programs.. Efinaconazole affords greater efficacy in milder disease, female patients, and those patients whose disease is relatively recent and confined to the great toenail, following 48 weeks' treatment. With longer treatment courses, similar results may be achieved in other subpopulations. Clinically meaningful results (a 40% improvement in the involvement of the diseased nail) were achieved with efinaconazole within six months in half the patients treated, and in over 90% of patients by study end. A greater proportion of female patients achieved clinically meaningful results at six months, although treatment success did not seem to be influenced by baseline disease severity.. The majority of patients treated with efinaconazole could expect to see clinically meaningful results within six months.

J Drugs Dermatol. 2016;15(10):1260-1266.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Follow-Up Studies; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Triazoles; Young Adult

To evaluate efficacy of efinaconazole topical solution, 10% in onychomycosis patients with early and long-standing disease.. An analysis of 1655 patients, aged 18-70 years, randomized to receive efinaconazole topical solution, 10% or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at Week 52. Three groups were compared: those with early disease (<1year), patients with a baseline disease of 1-5 years, and those with long-standing onychomycosis (>5years).. The majority of patients had long-standing disease; were older, male and white. While nail involvement of the target toenail did not differ noticeably amongst the three groups, the number of nails involved did increase progressively with disease duration. Differences were seen in terms of infecting pathogens in early disease that might have important treatment implications. Efinaconazole was more effective in treating early disease, however more than 40% of patients with long-standing disease were considered treatment successes.. A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis.. Treatment of onychomycosis early to avoid disease progression to other toenails is important. Once daily efinaconazole topical solution, 10% is particularly effective in these patients.

Topics: Administration, Topical; Adult; Antifungal Agents; Disease Progression; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Prospective Studies; Time Factors; Treatment Outcome; Triazoles

Successful treatment of onychomycosis is both a clinical and therapeutic challenge. Effective patient education and reassurance are critical. This post hoc analysis aims to provide some guidance to physicians based on initial disease severity and influencing factors.. A post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled studies evaluating the efficacy and safety of efinaconazole topical solution, 10% in mild to moderate onychomycosis. Outcomes were assessed based on baseline severity (20%-29%, 30%-39%, 40%-49%, and ≥50% affected target toenail).. Overall, the mean percent affected toenail following efinaconazole treatment decreased from 36.4% to 20.6% (a 43% reduction). The percent reduction in mean percent affected toenail (range, 43.6% to 59.8%) with efinaconazole was similar irrespective of baseline severity. Improvement was only seen in the very mildest patients with vehicle and not before week 36. Improvement was influenced by gender (females did better) and disease duration (long standing disease responding less well).. Our onychomycosis patients treated with efinaconazole might expect a 50% improvement in their disease within a year, and this will be seen as significant by many, especially those who have suffered for many years. Many will do better, but they will need to be reminded of the slow growth of the toenail.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Nails; Onychomycosis; Patient Satisfaction; Severity of Illness Index; Treatment Outcome; Triazoles; Young Adult

Transungual nail penetrance has traditionally been considered to be the only route of delivery for topical antifungals in onychomycosis. Subungual penetrance may be an alternate route of delivery.. To evaluate the ability of efinaconazole vehicle solution to reach the site of toenail onychomycosis through application to the hyponychium or hyponychium and dorsal nail surface, and assess the impact of the air gap between the nail plate and nail bed.. Twenty-three participants with moderate to severe, mycologically-confirmed onychomycosis were enrolled (mean age, 48.5 years). Two separate applications of vehicle solution containing fluorescein for visualization were applied at the hyponychium or hyponychium and dorsal nail surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the ventral surface of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application and after nail clipping.. There was a positive correlation between the size of the air gap and degree of affected nail involvement (R2=0.064). Assessments under both visible and UV light indicated that the vehicle had spread to the site of infection, with deposition of fluorescein wherever vehicle had reached, irrespective of application methodology or size of air gap. Nail clippings also indicated absorption into the ventral surface of the nail plate.. The relative contributions of subungual versus transungual application of drug to the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed.. This study suggests that the low surface tension vehicle developed for efinaconazole topical solution, 10% can reach the site of infection by application to the hyponychium, dorsal or ventral nail surface and nail folds. This multidirectional approach to drug delivery at the site of fungal infection may contribute to the magnitude of efficacy seen in clinical trials.

Topics: Administration, Cutaneous; Adult; Aged; Air; Antifungal Agents; Female; Fluorescein; Foot Dermatoses; Humans; Male; Middle Aged; Nails; Onychomycosis; Pharmaceutical Vehicles; Severity of Illness Index; Triazoles

To identify those patients who are more likely to achieve treatment success with efinaconazole topical solution 10% based on clinical improvement and mycological status during treatment.. A subgroup analysis of patients, aged 18 to 70 years, randomized to receive efinaconazole topical solution 10% or vehicle from 2 identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point, complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52 was evaluated based on mycologic cure at week 24, and the degree of clinical improvement in nail involvement at week 12.. Over a quarter (25.1%) of patients treated with efinaconazole topical solution 10% who could demonstrate at least 10% improvement in affected nail involvement by week 12 progressed to complete cures at week 52. Similarly, 21.7% of patients who demonstrated mycologic cure at week 24 achieved complete cures at week 52.. Early clinical improvement and mycologic clearance may help to predict treatment success with efinaconazole topical solution 10%.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Prognosis; Severity of Illness Index; Treatment Outcome; Triazoles; Young Adult

We sought to evaluate the efficacy of efinaconazole topical solution, 10%, in patients with onychomycosis and coexisting tinea pedis.. We analyzed 1,655 patients, aged 18 to 70 years, randomized (3:1) to receive efinaconazole topical solution, 10%, or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of the target toenail and negative potassium hydroxide examination and fungal culture findings) at week 52. Three groups were compared: patients with onychomycosis and coexisting interdigital tinea pedis on-study (treated or left untreated) and those with no coexisting tinea pedis.. Treatment with efinaconazole topical solution, 10%, was significantly more effective than vehicle use irrespective of the coexistence of tinea pedis or its treatment. Overall, 352 patients with onychomycosis (21.3%) had coexisting interdigital tinea pedis, with 215 of these patients (61.1%) receiving investigator-approved topical antifungal agents for their tinea pedis in addition to their randomized onychomycosis treatment. At week 52, efinaconazole complete cure rates of 29.4% were reported in patients with onychomycosis when coexisting tinea pedis was treated compared with 16.1% when coexisting tinea pedis was not treated. Both cure rates were significant compared with vehicle (P = .003 and .045, respectively), and in the latter subgroup, no patients treated with vehicle achieved a complete cure.. Treatment of coexisting tinea pedis in patients with onychomycosis enhances the efficacy of once-daily topical treatment with efinaconazole topical solution, 10%.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Onychomycosis; Tinea Pedis; Treatment Outcome; Triazoles; Young Adult

To evaluate efficacy, safety, and tolerability efinaconazole topical solution, 10% in diabetic patients with onychomycosis.. A post-hoc analysis of 112 patients, aged 29-70 years, randomized to receive efinaconazole topical solution, 10% or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52.. Mycologic cure rates (OC) were significantly greater with efinaconazole (56.5% and 56.3% in diabetic and non-diabetic patients respectively) compared to vehicle (P=0.016 and P<0.001, respectively). The primary end point, complete cure, was also greater for efinaconazole (13.0% and 18.8%, respectively vs 3.7% and 4.7%). Treatment success (percent affected target toenail ≤10%) for efinaconazole was 40.8% and 47.7%, respectively vs 18.5% and 18.2% with vehicle. There was no statistically significant difference between the diabetic and non-diabetic populations for any efficacy endpoint. Adverse events associated with efinaconazole were local site reactions and clinically similar to vehicle.. Once daily efinaconazole topical solution, 10% may provide a useful topical option in the treatment of diabetic patients with onychomycosis.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Diabetes Mellitus; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Triazoles

Effective transungual delivery of topical antifungal agents in onychomycosis has been hampered by poor nail permeation. To be effective they must have antifungal efficacy, and effectively permeate through the dense keratinized nail plate to the site of infection in the nail bed and nail matrix. The therapeutic efficacy of efinaconazole topical solution, 10% has been established in two phase 3 clinical trials in distal lateral subungual onychomycosis.. To investigate the transungual delivery of efinaconazole in onychomycosis patients and its fungicidal activity in the toenail.. Concentrations of efinaconazole were determined as part of a multi-center, open label study in forty onychomycosis patients following repeated application of efinaconazole topical solution, 5% and 10% to the toenails over 28 days, with a 2-week follow-up. Fungicidal activity against T. rubrum in the ventral layer of human nails was determined using an in vitro human nail infection model (ChubTur®).. Efinaconazole concentrations in the nail were four orders of magnitude higher than MIC values of efinaconazole against dermatophytes. Further, nail drug concentrations were not influenced by the presence of disease or nail thickness, and maintained at high antifungal levels post-treatment. Efinaconazole was effective in reducing fungal viability, suggesting that sufficient amounts of efinaconazole were being delivered into the ventral layer of the nail plate.
. Effective transungual delivery of efinaconazole was demonstrated. The high efinaconazole concentrations in patient toenails and fungicidal activity in vitro potentially contribute to the clinical efficacy reported in phase 3 studies.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Drug Delivery Systems; Female; Follow-Up Studies; Foot Dermatoses; Humans; In Vitro Techniques; Male; Microbial Sensitivity Tests; Middle Aged; Nails; Onychomycosis; Permeability; Triazoles; Trichophyton

To evaluate the ability of efinaconazole vehicle to reach the site of toenail onychomycosis by spreading through the subungual space between the nail plate and nail bed. Lacquer-based vehicles are primarily limited to application on the nail plate and dependent on nail plate permeation.. 11 patients (mean age 48.5 years) were entered with clinically determined onychomycosis. Presence of fungal infection was confirmed by KOH testing in eight patients. Two separate applications of vehicle (with fluorescein incorporated for better visualization) were applied at the hyponychium, avoiding application to the exterior nail plate surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the underside of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application, and after nail clipping.. Assessments under both visible and UV light indicated that the vehicle had spread into the subungual space, with deposition of flourescein wherever vehicle had reached, including in the nail bed. Nail clippings also indicated deposition to the underside of the nail plate.. The relative contributions of spreading into the subungual space, or permeation through the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed.. This study suggests that the vehicle developed for efinaconazole topical solution, 10%, when applied at the hyponychium, spreads into the subungual space between the nail plate and nail bed, reaching the site of infection.

Topics: Administration, Topical; Antifungal Agents; Female; Foot Dermatoses; Humans; Male; Middle Aged; Nails; Onychomycosis; Permeability; Treatment Outcome; Triazoles

To characterize the systemic exposure and pharmacokinetics of efinaconazole 10% solution and assess the potential for drug-drug interaction (DDI) in human volunteers and onychomycosis patients following topical administration.. Two single-center, open-label studies in healthy volunteers and severe onychomycosis patients. Efinaconazole 10% solution was applied topically to all 10 toenails (0.42 mL total daily dose volume); administered as single and then 7 daily doses to 10 healthy volunteers, and once daily for 28 days to 19 severe onychomycosis patients. Plasma concentrations of efinaconazole and its major metabolite H3 were determined by LC-MS-MS at multiple timepoints. Safety evaluations were carried out throughout both studies.. The mean peak plasma concentrations (Cmax) of efinaconazole and H3 were 0.54 and 1.63 ng/mL, respectively, in healthy volunteers; and 0.67 and 2.36 ng/mL, respectively, in patients. Both parent drug and metabolite accumulated following repeat dosing, and reached steady state in plasma by 14 days. Efinaconazole was well tolerated in both studies; no drug-related adverse events were reported.. Efinaconazole 10% solution resulted in very low systemic exposures to efinaconazole and H3 when applied topically at maximum use conditions to healthy volunteer and onychomycosis patients' toenails. Efinaconazole is a CYP inhibitor like other azole antifungals, and its lowest ki is 91 ng/mL for CYP2C9, a >130-fold higher concentration than the mean steady state Cmax observed in patients. The Cmax/ki ratio was 0.007, well below the threshold for clinical DDI evaluation as recommended in regulatory guidances, thereby suggesting efinaconazole 10% solution has remote potential for drug-drug interactions.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Interactions; Ethnicity; Female; Half-Life; Humans; Male; Middle Aged; Nails; Onychomycosis; Pharmaceutical Solutions; Triazoles; Young Adult

Onychomycosis is a common nail infection, often resulting in nail plate damage and deformity. Topical lacquer treatments have negligible efficacy. Oral treatments, although more efficacious, are limited by drug interactions and potential hepatotoxicity.. We investigated the safety and efficacy of efinaconazole 10% solution (efinaconazole), the first triazole antifungal developed for distal lateral subungual onychomycosis.. Two identical, multicenter, randomized, double-blind, vehicle-controlled studies were conducted in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement [study 1: N = 870, study 2: N = 785]). Patients were randomized (3:1) to efinaconazole or vehicle, once daily for 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52.. Mycologic cure rates were significantly greater with efinaconazole (study 1: 55.2%, study 2: 53.4%) compared with vehicle (P < .001). The primary end point, complete cure, was also significantly greater for efinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P < .001). Treatment success (percent affected target toenail [0%-≤10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from 17.9% to 40.2% in study 2, compared with 5.6% to 16.8% and 7.0% to 15.4%, respectively, with vehicle. Adverse events associated with efinaconazole were local site reactions (2%) and clinically similar to vehicle.. A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis.. Once daily topical efinaconazole appears to be a viable alternative to oral treatment options for onychomycosis.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Triazoles; Young Adult

Onychomycosis is a common nail infection that is difficult to treat successfully. The prevalence increases with age and is associated with diabetes. Oral treatments are limited by drug interactions and potential hepatotoxicity; topical treatments, by modest efficacy.. We investigated the efficacy and safety of a solution using a novel topical triazole antifungal, efinaconazole, in distal lateral subungual onychomycosis (DLSO).. Multicenter, randomized, double-blind, vehicle-controlled phase 2 study in mild to moderate toenail DLSO (n=135). Subjects randomized (2:2:2:1 ratio) to receive efinaconazole 10% solution (with or without semiocclusion), efinaconazole 5% solution, or vehicle, once daily for 36 weeks, with one 4-week posttreatment follow-up (week 40). Efficacy assessments included complete cure, mycologic cure, clinical efficacy, and other assessments of overall treatment effectiveness. No efficacy variables were designated as primary.. At follow-up, complete cure was numerically higher in all active groups (16%-26%) compared with vehicle (9%). Mycologic cure rates with efinaconazole 10% semiocclusion, efinaconazole 10%, and efinaconazole 5% were 83%, 87%, and 87%, respectively. Efinaconazole 10% (with or without semiocclusion) demonstrated significantly greater clinical efficacy and treatment effectiveness when compared with vehicle (P=.0088 and .0064; .0056 and .0085, respectively, for both efinaconazole 10% groups). Adverse events were generally similar and mild. Local-site reactions were restricted to few subjects and did not differ meaningfully from those produced by vehicle.. This study provided evidence that once-daily efinaconazole 10% solution (with or without semiocclusion) applied topically for 36 weeks was more effective than vehicle in treating DLSO and was well tolerated. Based on these results, efinaconazole 10% solution was chosen for the phase 3 development program.

Topics: Administration, Topical; Adult; Antifungal Agents; Chemistry, Pharmaceutical; Double-Blind Method; Female; Humans; Male; Middle Aged; Nails; Onychomycosis; Pharmaceutical Solutions; Research Design; Treatment Outcome; Triazoles; Young Adult

Topics: Administration, Topical; Antifungal Agents; Foot Dermatoses; Humans; Onychomycosis; Talaromyces; Triazoles

Toenail onychomycosis is a common condition that is equally challenging for podiatrists and patients. This case study documents a 26-year-old woman with bilateral total dystrophic onychomycosis of at least 5 years' duration. She had previously failed to respond to treatment with ciclopirox nail lacquer 8% and, despite hiding her condition with nail polish, was suffering from embarrassment, distress, and low self-esteem. At initial consultation, 100% of both great toenails was affected. After discussion of all treatment options, the patient opted for topical efinaconazole 10% solution, once daily for 48 weeks. Significant improvement was noted at the first (4-week) assessment period. This improvement was maintained through each subsequent virtual consultation, and complete cure was seen at a 30-week follow-up visit. To the author's knowledge, this is the first published report on the use of efinaconazole in total dystrophic onychomycosis. It suggests that the product may be effective in patients with even the most severe and treatment-recalcitrant disease, who are unwilling or unable to tolerate systemic antifungal therapy.

Topics: Administration, Topical; Adult; Antifungal Agents; Coronavirus; Female; Foot Dermatoses; Humans; Onychomycosis; Treatment Outcome; Triazoles

To be effective against onychomycosis, topically applied drugs have to reach the infection site at an effective concentration to exert antifungal activity against the parasitic form of dermatophytes. We established a novel in vitro method for predicting drug efficacy at the infection site and verified the method by comparing the efficacy of two azole class topical anti-onychomycosis drugs. To predict drug efficacy in the nail plate, a human nail permeability test was conducted and the activities of the free-drugs in the upper, middle, and lowest layers of the nail plate were determined by measuring the growth inhibitory zone. Efinaconazole permeated the nail more efficiently than luliconazole, and the amount of efinaconazole in the middle and lowest layers was higher compared with that of luliconazole. Efinaconazole demonstrated antifungal activities at the concentrations in all of the nail layers, whereas luliconazole was only active at the concentrations in the upper and middle layers. The results could be explained by differences in their affinity for keratin and nail permeability. The established method enables the evaluation of nail permeability and anti-arthrospore activity of free-drugs in the nail plate to predict drug efficacy. This method will be useful for new topical drug development.

Topics: Administration, Topical; Antifungal Agents; Humans; Imidazoles; Nails; Onychomycosis; Triazoles

Development of new topical drugs requires an animal onychomycosis model that can predict the drug efficacy against moderate to severe human onychomycosis because the severity of onychomycosis varies and affects the drug efficacy. This study established a non-immunosuppressive guinea pig tinea unguium model under 8-week infection condition in addition to a previously reported model under 4-week infection condition. In the tinea unguium model, most fungi were tightly present in the arthrospore form, like in human onychomycosis. The topical formulations of efinaconazole and luliconazole, two azole class anti-onychomycosis drugs, were evaluated for their efficacy in these models. In the untreated group, the nail fungal burden in the 8-week model was higher than that in the 4-week model and the stronger infection intensity affected the efficacy of the drugs, suggesting that the 8-week model was more severe. The 90% efficacy rate (42%) of luliconazole in the 8-week model was significantly lowered than that (83%) in the 4-week model, and its 99% efficacy rates were 0% in both models. Conversely, the 90% and 99% efficacy rates of efinaconazole (92% and 50% in the 4-week model, and 75% and 25% in the 8-week model, respectively) were not significantly different between the two infection durations. In addition, efinaconazole was more effective than luliconazole in reducing the nail fungal burden. Considering the relevance of clinical reports of the effectiveness of efinaconazole on severe onychomycosis, the new severe tinea unguium model would predict drug efficacy against moderate to severe onychomycosis.

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Guinea Pigs; Humans; Onychomycosis

The topical antifungal efinaconazole was applied to 27 nails (17 patients), and the treatment effects were monitored over a stipulated period (after 3, 6, and 12 months). Fourteen nails were observed for 18 months. Effects of the treatment were determined on the basis of the improvement rate of the turbidity ratio compared with that before treatment. After 12 months, five nails were cured and marked improvement was noted, whereas moderate and marked improvements were noted in 11 and six nails, respectively. The cured patients exhibited a significantly better improvement rate at 6 months (68.8%) than the other groups. Only 10.6% improvement was observed at the same point in time for the mild improvement group. Thus, in cases where the improvement rate after 6 months of treatment was 10% or less, it was judged that oral treatment should be considered. Furthermore, of the nails monitored for 18 months, those that exhibited further growth in improvement rates at 12 months was 51.6%, suggesting that an improvement rate of 50% at 12 months after starting treatment could be used as an indicator to determine switching to oral treatment.

Topics: Administration, Topical; Antifungal Agents; Humans; Onychomycosis; Triazoles

Topics: Administration, Topical; Age Factors; Antifungal Agents; Drug Prescriptions; Humans; Medication Adherence; Onychomycosis; Prescription Fees; Retrospective Studies; Triazoles

The onychomycosis treatment remains a big challenge for onychologist due to the shorter nail residence time of topical formulations and the lack of availability of novel formulations in markets for new generation antifungal drugs. The objective of this work was to design, develop, optimize, and evaluate microemulsion formulations for effective delivery of efinaconazole through transungual route in onychomycosis treatment. Capmul® MCM (Glyceryl Caprylate/Caprate) as oil, Labrasol® (caprylocaproyl polyoxyl-8 glycerides) as a surfactant, and Transcutol® P (diethylene glycol monoethyl ether) as co-surfactant exhibited higher solubility of efinaconazole and surfactant-cosurfactant mixture (Smix) in a ratio of 1:1 rendered higher microemulsion region in the pseudo-ternary phase diagram. The optimized microemulsion formulation containing 6%w/w oil phase, 22.5%w/w surfactant, 22.5%w/w co-surfactant, and 49%w/w demineralized water was converted into gel formulation using 1.0%w/w Carbopol® 934 P gelling agent and evaluated for stability of 6 months. The optimized microemulsion formulation globule size was less than 100 nm. The ex vivo permeation confirmed improved permeation of efinaconazole from microemulsion formulations (346.36±12.90μgcm

Topics: Antifungal Agents; Arthrodermataceae; Emulsions; Humans; Nails; Onychomycosis; Triazoles

The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-β-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 °C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.

Topics: Administration, Topical; Animals; Antifungal Agents; Cattle; Diffusion; Drug Carriers; Drug Delivery Systems; Hoof and Claw; Onychomycosis; Permeability; Propylene Glycol; Triazoles

Efinaconazole is a topical antifungal drug approved in Japan for tinea unguium. Although topical treatments generally have low cure rates with a prolonged therapy period, a Cochrane review confirmed that high-quality evidence supports the effectiveness of efinaconazole for the complete cure of tinea unguium. Combination therapy is a way to improve the cure rate of onychomycosis. In this study, topical efinaconazole was administrated to 12 patients who had been treated with oral terbinafine (125 mg daily) for more than 20 weeks with little expected effect. Because terbinafine accumulates for a long time in the nail, treatment immediately followed by other drugs can be considered sequential combination therapy. During terbinafine monotherapy, the percentage involvement decreased from 53.5% to 44.0% after 37.4 weeks and the effective and cure rates were 16.7% and 0%, respectively. During sequential topical efinaconazole therapy combined with lasting terbinafine in the nail, the percentage involvement decreased from 44.0% to 18.7% after 28.4 weeks, and the effective and cure rates were 66.7% and 16.7%, respectively. The improvement rate per month of combination therapy (12.6%) was higher than that with monotherapy (2.1%) (p = 0.002). There were no serious side-effects. This sequential combination therapy with efinaconazole was effective in poor terbinafine responders, making it a promising regimen for improving the cure rate of tinea unguium.

Topics: Administration, Topical; Antifungal Agents; Humans; Onychomycosis; Terbinafine; Triazoles

Onychomycosis with longitudinal spikes in the nail plate has been reported to be refractory to oral drugs as with dermatophytoma. We evaluated the efficacy of 10% efinaconazole solution in the treatment of onychomycosis with longitudinal spikes. Of the 223 subjects who were enrolled in a previous study, a post-hoc analysis of 82 subjects with longitudinal spikes was performed in this study. The opacity ratio of longitudinal spikes was decreased over time from 8.1 to 0.9 at the final assessment. In addition, the longitudinal spike disappearance rate increased early after the application to 81.7% at the final assessment. Therefore, 10% efinaconazole solution can be a first-line drug for longitudinal spikes, which have been regarded as refractory to oral drugs.

Topics: Administration, Topical; Antifungal Agents; Humans; Onychomycosis; Treatment Outcome; Triazoles

Onychomycosis is a chronic fungal infection of the nails and is commonly observed in adults, especially the elderly, those who are diabetic, have poor peripheral circulation, and are immunocompromised; however, onychomycosis in children is being reported more frequently, especially in older children. There could also be a genetic predisposition to developing onychomycosis. Given that onychomycosis is uncommon in children, it is important to confirm the diagnosis mycologically. Treatment of onychomycosis includes oral or topical antifungal agents. In North America, the available oral antifungal agents are terbinafine, itraconazole, and fluconazole; however, none of these agents are approved by Food and Drug Administration (FDA) for children with onychomycosis. Terbinafine is, however, approved for tinea capitis in children aged 4 years and older. In general, these oral agents have been found to be safe and effective for pediatric onychomycosis. The available topical agents are efinaconazole solution 10%, tavaborole solution 5%, and ciclopirox nail lacquer topical solution 8%. The former two are approved by the FDA for the treatment of pediatric onychomycosis in children aged 6 years and older, while the third one is approved in children over the age of 12 years who have onychomycosis. In a phase-IV, multicenter, open label study, efinaconazole solution 10% was administered to children aged 6-16 years with culture positive, mild-to-severe distal and lateral subungual onychomycosis affecting ≥20% of at least one great toenail. Treatment was for 48 weeks, with follow-up at week 52. Efinaconazole solution 10% was found to be safe and well tolerated in this pediatric population. By week 52, the mycological cure was 65%, and the complete cure was 40%. The topical agents could be an important addition to the armamentarium of therapies available to treat pediatric onychomycosis safely and effectively.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Child; Foot Dermatoses; Humans; Onychomycosis; Terbinafine; Triazoles

Topics: Administration, Topical; Antifungal Agents; Drug Costs; Foot Dermatoses; Healthy Volunteers; Humans; Nails; Onychomycosis; Solutions; Triazoles; United States

Topical onychomycosis therapy is commonly prescribed due to its tolerability and low incidence of side effects. There are limited data on adverse events associated with the newer topical onychomycosis drugs. The objectives of this study is to classify the most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution. The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for the most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution. Google Trends was used to examine public interest in these drugs and these data were compared with yearly adverse events in the FAERS database. The most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution were drug ineffectiveness. Application site erythema and nail discoloration were reported with all three medications. Increased Google searches for efinaconazole and tavaborole were associated with increased in reporting of adverse events to the FDA. Topical antifungals are safe alternatives for patients who have contraindications to oral medications. For improved efficacy, physicians should confirm the diagnosis of onychomycosis and choose appropriate candidates before starting topical therapy. Patients should be given clear instructions on drug usage and counseled about the more common side effects, including application site reactions and nail discoloration.

Topics: Administration, Topical; Adverse Drug Reaction Reporting Systems; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Erythema; Humans; Nails; Onychomycosis; Pigmentation; Retrospective Studies; Solutions; Treatment Failure; Triazoles; United States; United States Food and Drug Administration

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Guinea Pigs; Humans; In Vitro Techniques; Male; Membranes, Artificial; Nails; Onychomycosis; Permeability; Skin; Skin Absorption; Tinea; Triazoles; Trichophyton

Many clinicians prefer to treat onychomycosis systemically. However, systemic therapy may not be suitable for all onychomycosis patients due to drug interactions, side effects of oral medications, or comorbidities. Two topical agents (efinaconazole 10% in 2014 and luliconazole 5% in 2016) have recently been approved for treatment of onychomycosis in Japan. We investigated the efficacy of these topical agents at Teikyo University Mizonokuchi Hospital, Kanagawa, Japan. We conducted a retrospective survey among patients diagnosed with onychomycosis at our outpatient clinic and had been treated with either efinaconazole 10% solution or luliconazole 5% solution. Prior to commencement of treatment, the disease severity was evaluated using the Scoring Clinical Index for Onychomycosis (SCIO). Furthermore, the efficacies of these agents were evaluated using turbidity scoring at each visit to our outpatient clinic. Sixty-two patients (33 men, 29 women) applied efinaconazole 10% solution, and 72 patients (35 men, 37 women) applied luliconazole 5% solution. The mean SCIO scores were 18.1 and 17.4, respectively, and the mean 5-grade evaluation scores were 3.5 and 3.4, respectively. Complete cure rates were 40.3% (25/62) and 33.3% (24/72), respectively. The mean durations of treatment were 15.4 months and 11.9 months, respectively. There were no serious side effects in either treatment group. There were no significant differences between the two agents in improvement scores as assessed by the Tukey's test. Thus, efinaconazole 10% and luliconazole 5% topical solutions were effective for the treatment of onychomycosis. These topical agents may become important treatment options for this indication.

Topics: Administration, Topical; Adult; Aged; Female; Humans; Imidazoles; Male; Middle Aged; Onychomycosis; Retrospective Studies; Solutions; Treatment Outcome; Triazoles

Superficial fungal infections are one of the most common and burdensome skin problems affecting quality of life in patients. Various conventional antifungal agents have been used to treat fungal infections; however, various problems have been reported including drug interaction, drug resistance and low effectiveness. Efinaconazole is a novel antifungal agent, which has proven to be particularly effective against onychomycosis compared with conventional antifungal agents. However, the antifungal efficacy of Efinaconazole for specific strains has not been analysed.. We conducted an in-vitro study to measure the antifungal activity of Efinaconazole against strains of Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans compared with widely-used antifungal drugs.. We obtained strains of T. rubrum, T. mentagrophytes and C. albicans isolated from patients with onychomycosis and tinea pedis. The minimal inhibitory concentration (MIC) for various strains of fungal species was evaluated for the antifungal susceptibility test.. Efinaconazole showed a low MIC against almost strains of dermatophytes and C albicans and also presented low resistance, indicating high potency of efinaconazole for treatment of superficial fungal infections.. Efinaconazole could be a comparable alternative to replace existing conventional agents.

Topics: Antifungal Agents; Candida albicans; Humans; Microbial Sensitivity Tests; Onychomycosis; Tinea; Triazoles; Trichophyton

　Patients usually consult a dermatologist for the treatment of onychomycosis. However, in the case of home care, visiting nurses may assist with bathing, which offers the opportunity to observe patients' feet for possible signs of onychomycosis without causing anxiety. It is estimated that more than 30% of patients receiving home care have onychomycosis. Before the approval of efinaconazole, healthcare personnel hesitated to treat onychomycosis because of: 1) possible side effects, especially liver dysfunction and pain due to repeated blood collection, as a major goal of home care is to minimize pain; and 2) the questionable efficacy of previously available antifungal medications. In addition, many patients report fear of "transmitting athlete's foot to others" and "do not want to show my dirty toenails". On the other hand, caregivers reportedly worry about "athlete's foot being transmitted to them".

Topics: Antifungal Agents; Caregivers; Home Care Services; Humans; Infectious Disease Transmission, Professional-to-Patient; Onychomycosis; Triazoles

　There is an urgent need to promote home medical care in Japan because of the country's superaging society. Community pharmacists are expected to play an important role as part of home medical care teams. The prevalence of nail ringworm is high among home-care patients and can cause decreases in the quality of life, including difficulty in walking due to pain caused by nail deformation and inflammation around infected nails. Nail ringworm is typically treated with oral medication. However, the condition is left untreated in many elderly patients because of the risk of drug-drug interactions or concerns about severe liver damage. Efinaconazole, a novel triazole antifungal agent, has recently become available in Japan, enabling patients with nail ringworm to be treated with a topical medication. In topical treatment, the method of application is important because of its major impact on the therapeutic effect. Therefore, pharmacists should take special care to instruct patients and caregivers on the proper use of topical efinaconazole. Adherence to oral medication can be easily monitored by checking the number of tablets or capsules remaining, but adherence to topical medication regimens is more difficult to assess because the remaining amount cannot be determined precisely by checking the outer appearance of the container. The aim of this study was to determine and improve home-care patients' adherence to topical efinaconazole treatment regimens by measuring amounts remaining in the containers using a portable electronic scale. We found that this method is useful for determining the status of topical efinaconazole use.

Topics: Administration, Topical; Antifungal Agents; Community Pharmacy Services; Home Care Services; Humans; Japan; Onychomycosis; Patient Compliance; Pharmacists; Prevalence; Professional Role; Quality of Life; Triazoles

Topical antimicrobials are the ideal mode of onychomycosis treatment for efficient drug delivery and avoidance of sytemic effects associated with oral medications. However, high treatment costs, tissue penetration limitations, and low cure rates have continued to pose major challenges. To capitalize on the progress made by topical efinaconazole solution, efinaconazole was combined with inexpensive, previously-characterized nitric oxide releasing nanoparticles (NO-np), which have been shown to offer sustained nitric oxide release over time and enhanced barrier penetration, while exerting broad spectrum antimicrobial and immunomodulating properties. NO-np were combined with efinaconazole in varying concentrations and applied against reference strains of Trichophyton rubrum using a checkerboard method. Results demonstrated synergism of NO-np+efinaconazole against T. rubrum, which is noteworthy given the barriers present in the topical treatment of onychomycosis, and the multiple potential benefits offered by NO-np. Overall, this study illustrates the untapped potential of nanotechnology in the treatment of disorders of the skin, hair, and nails where drug delivery remains a challenge. J Drugs Dermatol. 2018;17(7):717-720.

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Drug Carriers; Drug Liberation; Drug Synergism; Drug Therapy, Combination; Humans; Mice; Microbial Sensitivity Tests; Nanoparticles; Naphthalenes; Nitric Oxide; Onychomycosis; Permeability; Prescription Fees; Terbinafine; Treatment Outcome; Triazoles; Trichophyton

We treated tinea unguium (onychomycosis caused by dermatophytes) patients with efinaconazole 10% solution. All patients with tinea unguium who tested positive for fungi in fingernails and toenails, regardless of age or severity, were eligible for the treatment. The number of patients was 106, consisting of 43 men and 63 women with a mean age of 66.7 years. The patients were treated with efinaconazole for a mean treatment duration of 38.1 weeks. Therapeutic efficacy was rated on a 5-point scale as follows: "cured", "markedly improved", "improved", "slightly improved" or "no change". A single nail was selected in each patient as the target nail. Selected nails were the big toenails with less than 50% involvement in 25 patients, the big toenails with 50% or more involvement in 52 patients, the fingernails in 10 patients and the second to fifth toenails in 19 patients with a mean treatment duration of 43.9, 38.1, 38.7 and 33.7 weeks, respectively. All groups showed an improvement in the percentage involvement from 30.6% to 9.8%, 77.6% to 35.7%, 82.7% to 17.6% and 80.3% to 15.5%, respectively (P < 0.01). The improvement rate (i.e. percentage of those rated as improved and better) was 76.0%, 65.4%, 80.0% and 89.5%, respectively. Efinaconazole 10% topical solution is beneficial for patients, regardless of age, severity or clinical type.

Topics: Administration, Topical; Aged; Aged, 80 and over; Antifungal Agents; Female; Foot Dermatoses; Hand Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Photography; Treatment Outcome; Triazoles

We describe a case of a 23-year-old female patient with no apparent underlying diseases. She showed a discoloration of the proximal portion of the left big toenail with paronychia. Direct microscopy revealed septate hyphae with conidiophores, and a periodic acid-Schiff-stained nail specimen revealed septate hyphae branching at angles of approximately 45°. On the basis of phylogenetic analysis, we finally arrived at the diagnosis of ungual aspergillosis caused by Aspergillus subramanianii. After p.o. administration of terbinafine and topical application of 10% efinaconazole solution, the disease resolved in 6 months. A. subramanianii is one of the new species in the genus Aspergillus section Circumdati. Reported clinical isolates have been isolated from lung tissue, wounds and feet. This is the first documented case of onychomycosis caused by A. subramanianii. Onychomycosis due to Aspergillus species is uncommon. We summarized the reported cases of ungual aspergillosis in Japan.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Antifungal Agents; Aspergillosis; Aspergillus; Female; Foot Dermatoses; Humans; Hyphae; Japan; Microscopy; Onychomycosis; Terbinafine; Triazoles; Young Adult

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Humans; Medication Adherence; Onychomycosis; Patient Education as Topic; Triazoles

Onychomycosis is a common progressive fungal infection of the nail bed, matrix, or plate leading to destruction and deformity of the toenails and fingernails. The prevalence of onychomycosis is increasing in the United States, particularly in the growing population of Latino patients. In this study, we evaluated the efficacy and safety of efinaconazole solution 10% in Latino patients with onychomycosis. Once-daily application of efinaconazole solution 10% may be an effective topical option for treatment of onychomycosis in this patient population.

Topics: Administration, Topical; Antifungal Agents; Female; Foot Dermatoses; Hispanic or Latino; Humans; Male; Middle Aged; Onychomycosis; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles; United States

There currently are 3 topical agents approved by the US Food and Drug Administration (FDA) to treat onychomycosis: tavaborole, efinaconazole, and ciclopirox. The phase 3 clinical trial designs for these treatments and their notable differences make it difficult for clinicians to interpret the data into clinical practice. For example, the primary end point predominantly used to assess efficacy in all the trials is complete cure, defined as no involvement of the nail plus mycologic cure; also, a notable number of patients fail to achieve a complete cure despite clear improvement in the nail. Despite close similarities in the end points and overall design of the clinical trials used for these agents, differences in design are notable, including the age range of participants, the range of mycotic nail involvement, the presence/absence of tinea pedis, and the nail trimming/debridement protocols used. The differences in clinical trial designs for the 3 FDA-approved topical agents and the lack of head-to-head studies makes efficacy interpretation and comparison inappropriate. This article reviews the phase 3 clinical trials that led to FDA approval of these agents, focusing on their similarities and differences.

Topics: Administration, Cutaneous; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Onychomycosis; Pyridones; Research Design; Treatment Outcome; Triazoles; United States

 Affinity of Luliconazole (LLCZ), an antifungal drug used for topical treatment of onychomycosis in Japan, to nail keratin was demonstrated. Efinaconazole (EFCZ) was used as a reference drug. Drugs at fixed concentrations were added to 4 ml of buffer solution containing 40 mg of nail keratin powder prepared from healthy volunteers or from tinea unguium patients. The mixtures were shaken at 37℃, and adsorption and desorption rates of the drug in nail keratin were measured. Theoretical analysis using the Freundlich adsorption isotherm was applied to eliminate effects of testing conditions on the results. Results showed that compared with EFCZ, LLCZ exhibited high adsorption rates and low desorption rates in nail keratins. These results were verified by Freundlich analysis, in which adsorption coefficient (K

Topics: Humans; Imidazoles; Keratins; Nails; Onychomycosis; Triazoles

Topics: Administration, Topical; Aged; Antifungal Agents; Aspergillosis; Female; Humans; Onychomycosis; Triazoles

Topics: Administration, Topical; Aged; Antifungal Agents; Dermatitis, Allergic Contact; Foot Dermatoses; Humans; Male; Nail Diseases; Onychomycosis; Patch Tests; Triazoles

Topics: Administration, Topical; Aged; Antifungal Agents; Dermatitis, Allergic Contact; Foot Dermatoses; Humans; Male; Onychomycosis; Patch Tests; Triazoles

Patients with onychomycosis may mask infected nails with polish. Tavaborole topical solution, 5% is a boron-based, small-molecule pharmaceutical approved for the treatment of toenail onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes; efinaconazole topical solution, 10% is approved for the same indication. Nail polish appearance after application of tavaborole (dropper) or efinaconazole (brush); respective applicator appearance; presence of color transfer from respective applicators; and color transfer to remaining solutions after dosing of polished nails were evaluated.. Twelve ex vivo human cadaver fingernails were cleaned, polished with two coats of L'Oréal® Nail Color, Devil Wears Red #420, and mounted on floral foam. Nails were treated with tavaborole or efinaconazole solutions once daily for 7 days. Dropper and brush applicators were applied to white watercolor paper immediately after dosing to evaluate color transfer from polished nails. On day 7, remaining solutions were transferred to clear glass vials to evaluate color transfer from applicators to solutions. Nails, applicators, and papers were photographed daily following application; remaining solutions were photographed after 7 days of dosing.. Tavaborole-treated polished nails showed no polish discoloration, and tavaborole applicators did not change in appearance during treatment. No color transfer from polished nails was evident to applicator, paper, or remaining solution. Efinaconazole-treated polished nails showed substantial polish changes after the first day of treatment, with polish appearance and discoloration progressively worsening over 7 days of treatment. Color transfer from nails was evident to applicator, paper, and remaining solution.. Daily dropper application of tavaborole to ex vivo polished nails did not alter polish appearance. Brush application of efinaconazole produced visible changes in polish appearance and color transfer to applicators, paper, and remaining solution. Tavaborole topical solution, 5% may not alter nail polish appearance; the impact of nail polish on tavaborole clinical efficacy has not been evaluated.

Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Nails; Onychomycosis; Triazoles

Onychomycosis is a fungal nail infection that is difficult to treat due to poor accessibility of drugs into the nail plate. Although oral antifungals can reach the nail apparatus more readily, these therapies may not be suitable or desirable for some patients (e.g., multiple medications or immunocompromised). Efinaconazole 10% solution is a new topical antifungal recently approved and sold in Canada, the United States and Japan for the treatment of mild-to-moderate toenail onychomycosis. Efinaconazole has broad-spectrum antifungal activity against dermatophytes, nondermatophyte molds and yeasts, and high ungual penetration due to its low keratin binding properties.. The objective of this article is to summarize recent data regarding the efficacy, safety and pharmacokinetic properties of efinaconazole in the treatment of onychomycosis.. Efinaconazole is a safe and effective treatment for onychomycosis that can be used in a wide range of patients due to its broad-spectrum antifungal activity and low rate of treatment-related adverse events. When incomplete response to oral therapy or devices (e.g. laser therapy) is encountered, efinaconazole could be used in combination to improve success rates. Alternatively, efinaconazole could be used as a 'closer' drug, in an effort to provide cure when the initial oral or device therapy has resulted in an incomplete response.

Topics: Antifungal Agents; Disease Management; Humans; Nails; Onychomycosis; Pharmaceutical Solutions; Triazoles

We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.

Topics: Adolescent; Adult; Antifungal Agents; Ciclopirox; Drug Interactions; Female; Humans; Keratins; Male; Middle Aged; Morpholines; Nail Diseases; Nails; Naphthalenes; Onychomycosis; Pharmaceutical Preparations; Pyridones; Solubility; Terbinafine; Triazoles; Young Adult

Recurrence (relapse or re-infection) in onychomycosis is common, occurring in 10% to 53% of patients. However, data on prevalence is limited as few clinical studies follow patients beyond 12 months. It has been suggested that recurrence after continuous terbinafine treatment may be less common than with intermittent or continuous itraconazole therapy, probably due to the fungicidal activity of terbinafine, although these differences tended not to be significant. Relapse rates also increase with time, peaking at month 36. Although a number of factors have been suggested to play a role in recurrence, only the co-existence of diabetes has been shown to have a significant impact. Data with topical therapy is sparse; a small study showed amorolfine prophylaxis may delay recurrence. High concentrations of efinaconazole have been reported in the nail two weeks' post-treatment suggesting twice monthly prophylaxis with topical treatments may be a realistic option, and may be an important consideration in diabetic patients with onychomycosis. Data suggest that prophylaxis may need to be continued for up to three years for optimal effect. Treating tinea pedis and any immediate family members is also critical. Other preventative strategies include avoiding communal areas where infection can spread (such as swimming pools), and decontaminating footwear.

Topics: Administration, Topical; Antifungal Agents; Comorbidity; Diabetes Mellitus; Drug Administration Schedule; Humans; Itraconazole; Morpholines; Naphthalenes; Onychomycosis; Prevalence; Recurrence; Terbinafine; Tinea Pedis; Triazoles

In 1996, oral terbinafine joined itraconazole and fluconazole on the short list of systemic medications that could be used to treat onychomycosis (although fluconazole was not approved for this indication by the US Food and Drug Administration [FDA], it was commonly used for this purpose). In 1999, ciclopirox was the first topical treatment to be FDA approved. The addition of the topical antifungal agents efinaconazole and tavaborole in 2014 expanded the roster of medications available to more effectively manage onychomycosis in a wide range of patients, including those for whom comorbid conditions, concomitant medications, or patient preference limited the use of systemic antifungals.

Topics: Administration, Cutaneous; Administration, Oral; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Fluconazole; Foot Dermatoses; Humans; Itraconazole; Naphthalenes; Onychomycosis; Pyridones; Terbinafine; Treatment Outcome; Triazoles; United States

Topics: Administration, Cutaneous; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Foot Dermatoses; Humans; Naphthalenes; Onychomycosis; Pyridones; Terbinafine; Treatment Outcome; Triazoles

Topics: Administration, Cutaneous; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Drug Administration Schedule; Foot Dermatoses; Humans; Onychomycosis; Pyridones; Triazoles

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cost-Benefit Analysis; Drug Costs; Female; Foot Dermatoses; Humans; Male; Onychomycosis; Sensitivity and Specificity; Severity of Illness Index; Triazoles

Onychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Two newly approved topical agents for onychomycosis are efinaconazole and tavaborole, both of which have demonstrated respectable cure rates in clinical studies. For tinea pedis, naftifine 2% and luliconazole 1% are new agents, both administered for relatively short courses, that may foster greater adherence Semin Cutan Med Surg 35(supp6):S110-S113.

Topics: Administration, Cutaneous; Antifungal Agents; Humans; Imidazoles; Onychomycosis; Recurrence; Tinea; Tinea Pedis; Triazoles

Efinaconazole 10% nail solution is a novel topical antifungal drug for the treatment of onychomycosis. Two Phase III trials were completed using efinaconazole 10% nail solution, where 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4% achieved mycological cure. Several post hoc analyses were carried out using data from Phase III trials to determine the efficacy of efinaconazole with respect to disease duration, disease progression, and comorbidities of diabetes or tinea pedis with onychomycosis. Efinaconazole produced higher efficacy rates with patients presenting onychomycosis in a small portion of the toenail (≤25%) for a shorter duration of time (<1 year and 1-5 years). When patients presenting with both onychomycosis and tinea pedis underwent concurrent treatment, efficacy of efinaconazole increased from 16.1% to 29.4%, suggesting combination therapy improved results. Most interestingly, there was no difference in efinaconazole efficacy between diabetic and non-diabetic groups, indicating efinaconazole could be a safe and effective form of treatment for diabetics. Overall, efinaconazole 10% nail solution shows potential as an antifungal therapy for the treatment of onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Clinical Trials, Phase III as Topic; Humans; Onychomycosis; Solutions; Triazoles

Two topical therapeutic agents were approved in Japan from 2015 to 2016, adding new options for onychomycosis therapy in the clinical field. In order to confirm the differences of formulation properties and nail pharmacokinetics between 5% luliconazole solution and 10% efinaconazole solution, drug concentration and antifungal activity in the nail were measured after topical treatment using human nail plates. In the in vitro permeation study, concentration of each drug was measured in the transversely sliced nail after single treatment with the two topical therapeutic agents. The results showed that concentration of luliconazole is higher than that of efinaconazole at all nail layers, differing by 1.7-8.4 times at each measurement point. Next, we examined antifungal activities of each drug in sliced nail after 14-day topical treatment. Mean rates of formation of inhibition zones for 5% luliconazole solution and 10% efinaconazole solution were 71.0% and 12.6%, respectively, and were statistically different. These results show that the two topical therapeutic agents have different properties, and suggest that 5% luliconazole solution has good nail permeation and retention characteristics. Moreover, luliconazole was found to retain enough antifungal activity in the nail plate against Trichophyton spp. after treatment with the topical agent.

Topics: Administration, Topical; Antifungal Agents; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Fungal; Humans; Imidazoles; In Vitro Techniques; Nails; Onychomycosis; Solutions; Triazoles; Trichophyton

Transungual drug delivery of antifungals is considered highly desirable to treat common nail disorders such as onychomycosis, due to localized effects, and improved adherence resulting from minimal systemic adverse events. However, the development of effective topical therapies has been hampered by poor nail penetration. An effective topical antifungal must permeate through, and under the dense keratinized nail plate to the site of infection in the nail bed and nail matrix. We present here the formulation development program to provide effective transungual and subungual delivery of efinaconazole, the first topical broad spectrum triazole specifically developed for onychomycosis treatment. We discuss the important aspects encompassing the formulation development program for efinaconazole topical solution, 10%, focusing on its solubility in a number of solvents, in vitro penetration through the nail, and in vivo efficacy. Efinaconazole topical solution, 10% is a stable, non-lacquer, antifungal with a unique combination of ingredients added to an alcohol-based formulation to provide low surface tension and good wetting properties. This low surface tension is believed to affect effective transungual delivery of efinaconazole and believed to provide a dual mode of delivery by accessing the nail bed by wicking into the space between the nail and nail plate.

Topics: Administration, Topical; Antifungal Agents; Chemistry, Pharmaceutical; Drug Delivery Systems; Foot Dermatoses; Humans; Nail Diseases; Nails; Onychomycosis; Permeability; Pharmaceutical Solutions; Solubility; Triazoles

Onychomycosis is a common nail infection that often co-exists with tinea pedis. Surveys have suggested the diseases co-exist in at least one third of patients, although actual numbers may be a lot higher due to significant under-reporting. The importance of evaluating and treating both diseases is being increasingly recognized, however, data on improved outcomes, and the potential to minimize re-infection are limited. We review a recent post hoc analysis of two large studies treating mild to moderate onychomycosis with efinaconazole topical solution, 10%, demonstrating that complete cure rates of onychomycosis are significantly improved when any co-existing tinea pedis is also treated.

Topics: Administration, Topical; Antifungal Agents; Clinical Trials as Topic; Humans; Onychomycosis; Severity of Illness Index; Tinea Pedis; Triazoles

Onychomycosis is a common fungal infection of the nail unit that results in discoloration, subungual debris, thickening, onycholysis, and often pain and impairment of mobility. Dermatophytomas are characterized by a thick fungal mass within and under the nail plate and are especially resistant to treatment. Here we report a case of a patient with a dermatophytoma who had failed oral terbinafine but was successfully treated with efinaconazole 10% topical solution.

Topics: Administration, Topical; Aged; Antifungal Agents; Foot Dermatoses; Humans; Male; Naphthalenes; Onychomycosis; Terbinafine; Tinea; Treatment Outcome; Triazoles

Topics: Administration, Topical; Antifungal Agents; Dermatitis, Allergic Contact; Humans; Male; Middle Aged; Onychomycosis; Patch Tests; Solutions; Triazoles

Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Debridement; Foot Dermatoses; Hand Dermatoses; Humans; Laser Therapy; Morpholines; Naphthalenes; Onychomycosis; Pyridones; Terbinafine; Triazoles

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.

Topics: Administration, Topical; Animals; Antifungal Agents; Guinea Pigs; Humans; In Vitro Techniques; Keratins; Microbial Sensitivity Tests; Nails; Onychomycosis; Tinea; Triazoles; Trichophyton

Efinaconazole 10% nail solution (Jublia(®)) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14α-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease.

Topics: 14-alpha Demethylase Inhibitors; Administration, Topical; Clinical Trials as Topic; Ergosterol; Humans; Microbial Sensitivity Tests; Onychomycosis; Triazoles

Efinaconazole is a novel triazole antifungal drug for the topical treatment of onychomycosis, a nail infection caused mainly by dermatophytes. We assessed the potential of efinaconazole to induce resistance in dermatophytes by continuous exposure of Trichophyton rubrum strains to efinaconazole in vitro (12 passages) and in a guinea pig onychomycosis model (8 weeks). There was no evidence of efinaconazole resistance development in the tested strains under the experimental conditions used.

Topics: Administration, Topical; Animals; Antifungal Agents; Colony Count, Microbial; Drug Resistance, Fungal; Guinea Pigs; Microbial Sensitivity Tests; Onychomycosis; Triazoles; Trichophyton

Efinaconazole is a triazole developed as a 10% solution for topical treatment of onychomycosis, a common fungal nail infection. Efinaconazole solution and topical formulation vehicle administered dermally to mice (13weeks), rats (6months) and minipigs (9months) produced transient erythema, minimal to modest hyperkeratosis, and mild microscopic skin inflammation. The liver was the target organ of systemic toxicity; reversible, minimal to moderate vacuolated changes were noted in the rat dermal study at 15 and 50mg/kg/day. No systemic toxicity was observed in mice and minipigs, at approximate high dermal doses of 930 and 170mg/kg/day, respectively. Daily subcutaneous injection of propylene glycol vehicle or efinaconazole to rats for 6months produced severe local inflammation and systemic spread, evidenced by peritoneal adhesions, spinal cord necrosis and urinary tract disease. Mortalities occurred in all groups but were increased at the high dose (30 or 40mg/kg/day), suggesting that vehicle effects were exacerbated by efinaconazole. Efinaconazole was not carcinogenic in a 2-year mouse dermal study and was not genotoxic. Exposure-based safety margins at the NOAEL were 70-698 relative to onychomycosis patients. In conclusion, efinaconazole demonstrated low/moderate toxicity, consistent with other azole antifungals, and high safety margins for topical onychomycosis therapy.

Topics: Administration, Cutaneous; Administration, Topical; Animals; Antifungal Agents; Dose-Response Relationship, Drug; Female; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; No-Observed-Adverse-Effect Level; Onychomycosis; Pharmaceutical Solutions; Rats; Rats, Sprague-Dawley; Skin; Swine; Swine, Miniature; Time Factors; Triazoles

Topics: Administration, Topical; Antifungal Agents; Drug Approval; Humans; Onychomycosis; Triazoles; United States; United States Food and Drug Administration

Onychomycosis, a common nail infection that often is associated with substantial patient distress, disability, and pain, is a challenge to manage successfully. This report presents the case of a 44-year-old man with moderate distallateral subungual onychomycosis (DLSO) of more than 5 years' duration and discusses effective treatment with efinaconazole solution 10%, a new topical antifungal, once daily for 48 weeks. At baseline, 50% of the great toenail was affected and laboratory test results were positive for Trichophyton rubrum. Mycologic cure was noted at week 36 with complete cure observed at the end of treatment (week 48). This case demonstrates for physicians that efinaconazole solution 10% is a promising new topical treatment of onychomycosis and emphasizes the importance of mycologic cure as an early indicator of treatment success.

Topics: Adult; Antifungal Agents; Foot Dermatoses; Humans; Male; Onychomycosis; Triazoles; Trichophyton

Toenail onychomycosis is a common disease with limited treatment options, as treatment failures and relapses frequently are encountered. Many patients experience long-term disease that affects multiple toenails and causes substantial discomfort and pain. Although many patients prefer topical therapies, treatment efficacy with ciclopirox and amorolfine lacquers has been disappointing. Efinaconazole solution 10% is a new triazole antifungal agent specifically developed for the treatment of onychomycosis. Efinaconazole has shown a broad spectrum of antifungal activity in vitro and is more potent than ciclopirox against common onychomycosis pathogens. It has lower keratin binding and quicker drug release from keratin than ciclopirox and amorolfine and exhibits remarkably greater in vivo activity. Efinaconazole has limited or no potential for drug interactions and a low resistance potential. Efinaconazole provides a viable alternative to oral therapy for the treatment of toenail onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Foot Dermatoses; Humans; Onychomycosis; Recurrence; Triazoles

A non-lacquer 10% topical solution of efinaconazole, developed by Valeant Pharmaceuticals International, received its first global approval in Canada in October 2013 for the treatment of onychomycosis. The product is under regulatory review in the US and Japan. The mechanism of anti-fungal activity of efinaconazole, a small-molecule triazole compound, appears to be similar to that of other anti-fungal triazoles, namely ergosterol synthesis inhibition. In particular, it appears to inhibit 14α demethylase, an enzyme involved in the conversion of lanosterol to ergosterol, resulting in secondary degenerative changes. This article summarizes the milestones in the development of efinaconazole leading to this first approval for onychomycosis.

Topics: Administration, Topical; Animals; Antifungal Agents; Drug Approval; Humans; Onychomycosis; Pharmaceutical Solutions; Triazoles

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 μg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 μg/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from ≤ 0.0005 to >0.25 μg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 μg/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.

Topics: Antifungal Agents; Aspergillus; Candida; Cryptococcus; Itraconazole; Microbial Sensitivity Tests; Morpholines; Naphthalenes; Onychomycosis; Pseudallescheria; Scopulariopsis; Terbinafine; Triazoles; Trichophyton; Trichosporon

The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8- and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.

Topics: Administration, Oral; Administration, Topical; Animals; Antifungal Agents; Guinea Pigs; Male; Microbial Sensitivity Tests; Morpholines; Naphthalenes; Onychomycosis; Terbinafine; Tinea Pedis; Triazoles; Trichophyton