tavaborole and Onychomycosis

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

Topics: Animals; Boron Compounds; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Drug Design; Humans; Multiple Myeloma; Onychomycosis

Onychomycosis is a fungal infection of the nail primarily caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The topical-based treatment of onychomycosis remains a challenge because of the difficulty associated with penetrating the dense, protective structure of the keratinized nail plate. Tavaborole is a novel small-molecule antifungal agent recently approved in the United States for the topical treatment of toenail onychomycosis. The low molecular weight, slight water solubility, and boron chemistry of tavaborole maximize nail penetration after topical application, allowing for effective targeting of the infection in the nail bed. The efficacy of tavaborole is associated with its novel mechanism of action, whereby it inhibits the fungal leucyl-tRNA synthetase (LeuRS) enzyme. Because LeuRS is an essential component in fungal protein synthesis, inhibition of LeuRS ultimately leads to fungal cell death. Tavaborole is the first boron-based antifungal medication approved for the treatment of mild-to-moderate onychomycosis and presents patients with a new topical option. Previously, ciclopirox and efinaconazole were the only approved topical treatments for onychomycosis. This article details the properties that are at the core of the clinical benefits associated with tavaborole.

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Microbial Sensitivity Tests; Nails; Onychomycosis; Treatment Outcome

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

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 a fungal nail infection that accounts for half of all nail diseases. Oral drugs on the market have adverse effects, while it is difficult for traditional topical drugs to penetrate the nail plate to reach the diseased nail bed. Tavaborole is a new drug that addresses the unmet needs of currently available treatments. Tavaborole (5%) is FDA approved for treating toenail onychomycosis and has shown antifungal activities against yeast, moulds and dermatophytes.. The objective of this article is to review the efficacy, pharmacokinetics, pharmacodynamics, and safety of tavaborole for treatment of toenail onychomycosis. Expert commentary: Tavaborole, with its unique mechanism, may be a good candidate for use in treating children with fungal infections, diabetic individuals, and treating mixed infections. Tavaborole may be paired with other therapies to potentially increase cure rates.

Topics: Administration, Topical; Animals; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Foot Dermatoses; Humans; Onychomycosis

Topics: Administration, Topical; Animals; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Foot Dermatoses; Humans; Onychomycosis; Pharmaceutical Solutions

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

Tavaborole topical solution, 5% (tavaborole) is a novel, boron-based, antifungal pharmaceutical agent indicated for treatment of toenail onychomycosis due to the dermatophytes Trichophyton rubrum or Trichophyton mentagrophytes. In preclinical studies, tavaborole effectively penetrated through full-thickness, non-diseased cadaver fingernails, including those with up to four layers of nail polish. Limited systemic absorption was observed following topical application of tavaborole. In phase III clinical trials involving patients with distal subungual onychomycosis affecting 20-60% of a target great toenail, significantly more patients treated with tavaborole versus vehicle achieved completely clear nail with negative mycology following daily application for 48 weeks. Treatment-emergent adverse events reported by at least 1% of patients treated with tavaborole and at a greater frequency versus vehicle included ingrown toenail, exfoliation, erythema and dermatitis. Treatment discontinuations were uncommon. Results from preclinical studies and phase III clinical trials establish tavaborole as a safe and efficacious treatment for toenail onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Interactions; Foot Dermatoses; Humans; Onychomycosis; Solutions

Onychomycosis is a fungal nail plate infection that has been increasing in prevalence. A variety of oral and topical anti-fungal agents are currently available but their use is limited by their adverse effect profile, drug-drug interactions, and limited efficacy. Therefore, there is a great need for newer anti-fungal agents. Tavaborole is one of these newer agents and was approved by the US Food and Drug Administration in July 2014 for the topical treatment of mild to moderate toenail onychomycosis. Tavaborole is a novel, boron-based anti-fungal agent with greater nail plate penetration than its predecessors, due to its smaller molecular weight. It has proven through several Phase II and III trials that it can be a safe and effective topical agent for the treatment of mild to moderate toenail onychomycosis without the need for debridement. In this paper, we review the landscape of topical and systemic treatment of onychomycosis, with particular attention to the pharmacokinetics, safety, and efficacy of topical tavaborole.

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Foot Dermatoses; Humans; Onychomycosis; United States; United States Food and Drug Administration

Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection.

Topics: Administration, Cutaneous; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Compounding; Foot Dermatoses; Humans; Onychomycosis

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 challenging nail disease that is difficult to treat due to the thickness and impermeability of the nail plate. At present, systemic agents are the first-line of treatment for this type of infection; however, topical treatment is recommended in milder cases (<50% involvement) or when oral treatment is contraindicated. Effective topical treatments capable of penetrating the nail plate and reaching the site of infection continue to be sought. Tavaborole, the first member of a new class of boron-containing antifungals, is a lightweight, water-soluble topical nail solution for the treatment of toenail onychomycosis. Tavaborole has a unique mechanism of action against fungal organisms and retains antifungal properties in the presence of keratin. Tavaborole 5.0% nail solution has shown a favourable safety and efficacy profile in Phase II/III clinical trials and is currently under review for licensing in the US by the US Food and Drug Administration.

Topics: Adult; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Foot Dermatoses; Humans; Onychomycosis

Onychomycosis is a fungal infection of the fingernails and toenails that results in thickening, discoloration, splitting of the nails and lifting of the nail from the nail bed. The disease is caused by dermatophytes and has a high incidence within the general population, especially among older individuals. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes; however, neither of these treatment options provides high cure rates that are durable. The difficulty in treating onychomycosis results from the deep-seated nature of the infection within the nail unit (nail plate, nail bed and surrounding tissue) and the inability of drugs to effectively reach all sites. Ongoing drug development activities have focused on novel delivery technologies to facilitate penetration of existing antifungal drugs through the nail plate and on the discovery of inherently penetrable antifungals. AN-2690 represents an oxaborole antifungal that is designed to penetrate the nail plate and is showing promising results in clinical trials.

Topics: Administration, Topical; Animals; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Foot Dermatoses; Hand Dermatoses; Humans; Onychomycosis

Schering-Plough Corp, under license from Anacor Pharmaceuticals Inc, is developing AN-2690, an antifungal agent with activity against Trichophyton species, in a topical solution formulation, for the potential treatment of onychomycosis. Phase II and IIb trials with AN-2690 are underway.

Topics: Administration, Topical; Animals; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Onychomycosis; Structure-Activity Relationship; Trichophyton

Background: This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of tavaborole in pediatric patients.\ Study Design: In this open-label, single-arm study, pediatric patients (aged 6 to <17 years) with distal subungual onychomycosis affecting ≥20% of the target great toenail applied tavaborole once daily to all affected toenails (2 drops/great toenail, 1 drop/other toenail) for 48 weeks. In addition, a maximal-use subgroup (aged 12 to <17 years) applied tavaborole to all 10 toenails and ≤2 mm of surrounding skin for the first 28 days.\ \ Results: Treatment-emergent adverse events (TEAEs) were reported by 55.6% of patients; the most frequently reported (≥5% of patients) were nasopharyngitis, contusion, sinusitis, and vomiting. Most TEAEs and local treatment reactions (LTRs) were mild or moderate and considered unrelated to treatment. There was 1 serious AE (severe appendicitis, considered unrelated to treatment) and there were no deaths, discontinuations because of AEs, or dose adjustments because of AEs. The most frequently reported LTRs were erythema and scaling. The incidence of LTRs diminished over time. Tavaborole was absorbed systemically, and plasma concentrations were measurable. The PK parameters determined in this study under maximal-use conditions indicate that steady state was achieved within the study period. For efficacy, 8.5% of patients achieved complete cure (clear nail and negative mycology [negative fungal culture and negative potassium hydroxide wet mount]) at week 52, and 14.9% achieved complete/almost complete cure at week 52 (clear or almost clear nail [≤5% dystrophic or discolored distal toenail plate] and negative mycology).\ \ Conclusion: Tavaborole was well tolerated in this pediatric population, and safety, PK, and efficacy profiles were comparable with those in adults.\ \ Trial registration: ClinicalTrials.gov identifier: NCT03405818\ \ J Drugs Dermatol. 2019;18(2):190-195.

Topics: Administration, Topical; Adolescent; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Drug Compounding; Female; Foot Dermatoses; Humans; Male; Onychomycosis; Pharmaceutical Solutions; Treatment Outcome

The role of topical antifungal agents in the long-term management of toenail onychomycosis is not well established. The current study evaluated durability of clinical benefit of tavaborole topical solution, 5%, for the treatment of toenail onychomycosis.. We conducted a pooled analysis of 8-week, post-study follow-up (PSFU) data from two phase 3, randomized controlled trials in a subset of patients who experienced complete or almost clear nail (CN) at the end of treatment (week 52); 48 weeks of treatment with once-daily tavaborole compared with placebo in adults with distal subungual onychomycosis was evaluated at week 60. Complete cure (completely CN plus negative mycology) of the target great toenail and treatment success (<10% nail involvement plus negative mycology) were evaluated at week 52 versus week 60.. Of the 62 patients who completed the PSFU, complete cure was higher in the tavaborole-treated group versus the vehicle control group (28.6% vs. 7.7%). Additionally, treatment success was 53.1% for the tavaborole group versus 23.1% in the vehicle group. Small sample size entering the PSFU limited robust statistical analysis.. Tavaborole topical solution, 5%, appears to provide durable clinical benefit, making it an attractive long-term treatment option for dermatophyte-associated onychomycosis of the toenail.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Foot Dermatoses; Humans; Hypertension; Male; Middle Aged; Onychomycosis; Placebo Effect; Treatment Outcome

Women with onychomycosis may suffer more effects on their quality of life than men. There is limited female-specific data on the treatment of onychomycosis. Tavaborole is a topical treatment option for onychomycosis. This post-hoc study evaluated the nail plates of women using data from the tavaborole 5% Phase III studies at baseline and end of study for the areas of healthy nail and infected nail. Over 52 weeks (48-week treatment, 4-week follow up), women treated with tavaborole had an average 32% increase in healthy nail and 21% decrease in infected nail. Patients with baseline infection involving >50% of the nail plate had an average increase in percentage of unaffected nail surface area of 81% and a corresponding 51% decrease in infected nail. These analyses suggest that patients with the greatest toenail involvement at baseline had greater overall improvements than those who were less affected. This evaluation provides additional clinical guidance for treating women with onychomycosis using tavaborole. J Drugs Dermatol. 2018;17(2):168-172.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Foot Dermatoses; Humans; Middle Aged; Onychomycosis; Treatment Outcome; Young Adult

Dermatophytoma is a little-known, difficult to treat fungal infection that complicates onychomycosis. First described by Roberts and Evans in the late 1990's, dermatophytoma presents as a dense concentration of fungal hyphae within or under the nail plate and is generally white or yellow/brown in color, and linear (streaks) or round (patches) in shape; primary etiologic organisms are dermatophytes. Oral antifungals have limited success in treating dermatophytoma owing to difficulties accessing and penetrating what is hypothesized to be a fungal biofilm. In this respect, dermatophytoma is generally treated with a combination therapy approach, often including both surgical and pharmacologic intervention for improved outcomes. A post-hoc assessment of Phase II tavaborole onychomycosis studies was conducted in order to assess the prevalence of dermatophytoma and outcomes in patients treated with topical tavaborole. Of the 366 subjects enrolled in the Phase II onychomycosis studies, we identified 102 cases of dermatophytoma; 21 of 86 (24.4%) subjects treated with tavaborole were able to achieve complete resolution of dermatophytoma by day 180, while no subjects on vehicle obtained resolution. Similarly, 23 of 86 subjects (26.7%) treated with tavaborole solution had complete resolution of dermatophytoma by day 360, while only 1 of 16 subjects (6.3%) on vehicle obtained resolution. Moreover, 13 of 19 subjects (68.4%) treated with tavaborole solution were able to sustain resolution, while only 6 of 19 (31.6%) had reoccurrence, of dermatophytoma during the 180-day washout period (day 360). We present 5 cases of dermatophytoma identified in Phase II trials that responded in a positive manner following treatment with tavaborole solution for onychomycosis of the great toenail. Although not representative of all subject outcomes, these findings provide insight into the use of topical tavaborole for dermatophytoma, a condition previously thought to respond only to oral or combination therapy.

J Drugs Dermatol. 2018;17(3):347-354.

Topics: Administration, Topical; Adult; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome

Toenail onychomycosis is a chronic fungal infection that often requires prolonged treatment in order to effectively manage pathogenic organisms and obtain a clear nail. Traditionally, certain clinical features of onychomycosis, including the presence of substantial lateral disease, focal fungal masses, yellow/brown streaks, and extensive nail involvement (ie, >50%), indicate a poor treatment prognosis and have proven difficult-to-treat with oral or traditional topical therapies. Owing to the novel features of topical tavaborole, we sought to understand the potential utility of tavaborole in difficult-to-treat onychomycosis. A blinded, post-hoc assessment of Phase III trials was conducted, focusing on initial presentation, midpoint assessment (24 weeks), and final outcomes (52 weeks) in subjects identified as having difficult-to-treat onychomycosis and treated for 48 weeks with once-daily application of either tavaborole 5% solution or vehicle. Our post-hoc analysis identified 84 difficult-to-treat cases (tavaborole 5%; n=60; vehicle, n=24) in subjects with toenail onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes. No subjects identified as difficult-to-treat and treated with vehicle achieved a complete cure, while 6 subjects treated with tavaborole 5% attained a completely clear nail and negative mycology. Similarly, 7 subjects treated with tavaborole 5% solution achieved an almost complete cure (≤10% involvement and negative mycology) while 1 subject on vehicle achieved an almost complete cure. We present a case series of 4 patients, of varying age and difficult-to-treat clinical features, which responded positively to tavaborole 5% solution. Three of the subjects achieved complete cure after being treated with tavaborole 5%, with one additional subject (an 88-year-old female) achieving an almost complete clear nail by treatment end. The outcomes presented here may not be reflective of patients that may present with these clinical characteristics. Additional investigations would be useful in order to assess the value of topical tavaborole 5% solution in difficult-to-treat clinical presentations of onychomycosis.

J Drugs Dermatol. 2017;16(10):1016-1021.

Topics: Administration, Topical; Adult; Aged, 80 and over; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Onychomycosis; Treatment Outcome

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

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

Onychomycosis, a fungal nail infection, can impact quality of life.. We sought to evaluate the efficacy and safety of tavaborole topical solution, 5% for treatment of toenail onychomycosis.. In 2 phase-III trials, adults with distal subungual onychomycosis affecting 20% to 60% of a target great toenail were randomized 2:1 to tavaborole or vehicle once daily for 48 weeks. The primary end point was complete cure of the target great toenail (completely clear nail with negative mycology) at week 52. Secondary end points included completely or almost clear nail, negative mycology, completely or almost clear nail plus negative mycology, and safety.. Rates of negative mycology (31.1%-35.9% vs 7.2%-12.2%) and complete cure (6.5% and 9.1% vs 0.5% and 1.5%) significantly favored tavaborole versus vehicle (P ≤ .001). Completely or almost clear nail rates also significantly favored tavaborole versus vehicle (26.1%-27.5% vs 9.3%-14.6%; P < .001). Rates of completely or almost clear nail plus negative mycology (15.3%-17.9% vs 1.5%-3.9%) were significantly greater for tavaborole versus vehicle (P < .001). Application-site reactions with tavaborole included exfoliation (2.7%), erythema (1.6%), and dermatitis (1.3%).. Duration of follow-up is a limitation.. Tavaborole demonstrates a favorable benefit-risk profile in treatment of toenail onychomycosis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Young Adult

To assess the potential efficacy, safety, and optimal dosing concentration of tavaborole, a novel, boron-based pharmaceutical agent with broad-spectrum antifungal activity, for the treatment of onychomycosis of the toenail due to dermatophytes.. One double-blind, randomized, vehicle-controlled study (study 1) and two open-label studies (studies 2 and 3) examined the efficacy, safety, and optimal dosing concentration of tavaborole topical solution applied once daily or three times weekly for 180 days at concentrations of 1.0%, 2.5%, 5.0%, or 7.5%. Patient cohort 3 of study 2 received open-label tavaborole 5.0% once daily for 360 days. All three studies assessed day 180 treatment success, defined as complete or partial clinical evidence of clear nail growth plus negative fungal culture.. A total of 336 patients were included in the intent-to-treat (ITT) or modified ITT populations and efficacy analyses across the 3 studies. In study 1, treatment success rates at day 180 were higher with tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (27%, 26%, and 32% vs 14%, respectively; slope P=0.030). In cohort 3 of study 2, 7% of patients achieved treatment success with tavaborole 5.0% at day 360. Negative culture rates at day 180 in study 1 were numerically higher for tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (slope P=0.046). Application-site reactions of general irritation, erythema, scaling, and stinging/burning were most common with tavaborole 7.5%, were generally mild to moderate, and resolved with treatment discontinuation and/or a reduction in dosing frequency. No systemic safety concerns were observed.. Tavaborole solution demonstrated favorable efficacy and safety in phase 2 clinical studies. Based on these findings, tavaborole topical solution, 5% was further investigated in larger, more definitive phase 3 studies. Results from these completed phase 3 studies will provide additional evidence regarding the safety and efficacy of tavaborole in the treatment of toenail onychomycosis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Antifungal Agents; Boron; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Erythema; Female; Foot Dermatoses; Humans; Male; Middle Aged; Onychomycosis; Treatment Outcome; Young Adult

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

Topical antifungal treatments for onychomycosis are applied to clean, unpolished nails for 48 weeks or longer. Patients often wish to mask their infection with nail polish yet there is no evidence to suggest antifungal efficacy in the presence of nail polish.. To determine if tavaborole retains the ability to penetrate the nail plate and inhibit fungal growth in the presence of nail polish.. Tavaborole was applied to human fingernails painted with 2 or 4 coats of nail polish, and unpainted nails in an ex vivo model. Nails were mounted on TurChub. Tavaborole exhibited antifungal activity in all experimental groups. The zones of inhibition of T. rubrum for all experimental groups (2 or 4 coats of polish, unpolished) were greater than infected controls (polished and unpolished), p

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cosmetics; Drug Compounding; Humans; Models, Biological; Onychomycosis; Trichophyton

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Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Fungi; Humans; Microbial Sensitivity Tests; Onychomycosis; Yeasts

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

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

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

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively.

Topics: Administration, Cutaneous; Animals; Animals, Newborn; Antifungal Agents; Boron; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Embryonic Development; Female; Fertility; Fetal Development; Male; Onychomycosis; Rabbits; Rats; Reproduction; Toxicity Tests

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

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/d from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/d dose group. Excess salivation was observed in the 60 and 100 mg/kg/d dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/d, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was ≥100 mg/kg/d, based on the lack of test article-related changes.

Topics: Administration, Topical; Animals; Animals, Newborn; Body Weight; Boron; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Embryonic Development; Female; Fertility; Fetal Development; Male; Maternal Exposure; No-Observed-Adverse-Effect Level; Onychomycosis; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests

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

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Itraconazole; Onychomycosis; Remission Induction; Toes

An effective topical antifungal medication must penetrate through the nail plate at sufficient concentrations to eradicate the fungal infection. Tavaborole topical solution, 5% is a novel boron-based pharmaceutical approved for the treatment of toenail onychomycosis due to Trichophyton rubrum or T mentagrophytes. Four in vitro studies assessed the antifungal activity and nail penetration of tavaborole. In Study 1, tavaborole demonstrated minimum inhibitory concentration (MIC) values ranging from 0.25-2 μg/mL against all fungi tested; addition of 5% keratin powder did not affect the MIC against T rubrum. The minimum fungicidal concentration (MFC) values for tavaborole against T rubrum and T mentagrophytes were 8 and 16 μg/mL, respectively. In Study 2, tavaborole effectively penetrated through the nail plate; mean concentrations in the ventral/intermediate nail layer were significantly higher than ciclopirox at day 15. In Study 3, mean cumulative tavaborole penetration through ex vivo human nails was significantly higher than ciclopirox at day 15. In Study 4, tavaborole demonstrated superior nail penetration and fungicidal activity, as measured by zones of inhibition. These studies demonstrated the superior penetration of tavaborole through the nail plate vs ciclopirox. Tavaborole demonstrated robust antifungal activity, with low MIC and MFC values, even in the presence of keratin.

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ciclopirox; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Nails; Onychomycosis; Pyridones

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 causes approximately one-half of all nail disorders and its prevalence has been steadily increasing. It is difficult to treat, partly due to the subungual location and the inability of both oral and topical antifungals to reach the site of infection. Published cure rates with oral drugs are < 50% and even lower with topical drugs. Pathogenic factors include the diversity of fungal organisms and the difficulty of drugs penetrating the nail plate. Tavaborole is a broad-spectrum oxaborole antifungal agent with low molecular weight, permitting optimal nail plate penetration. In vitro and ex vivo studies have demonstrated the superior nail-penetrating properties of tavaborole compared to existing topical antifungal medications approved for the treatment of onychomycosis.. The clinical characteristics and prevalence of onychomycosis, currently available treatments, and the chemistry, safety and pharmacokinetic properties of tavaborole for the treatment of onychomycosis.. Tavaborole is a novel, topical antifungal pharmaceutical agent pending FDA approval for the treatment of toenail onychomycosis due to dermatophytes. Efficacy has been demonstrated by a clinical development program including in vitro data and two large Phase III trials that enrolled ∼ 1200 patients. When approved, tavaborole topical solution, 5% may become a safe and effective option for the treatment of onychomycosis.

Topics: Administration, Topical; Anti-Infective Agents, Local; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Nails; Onychomycosis; Permeability; Pharmaceutical Solutions

Tavaborole is a novel, low-molecular weight oxaborole antifungal drug under development by Anacor Pharmaceuticals Inc. for the topical treatment of onychomycosis of the toenail. The drug has received its first global approval for this indication in the US. This article summarizes the milestones in the development of tavaborole leading to this first approval for onychomycosis of the toenails.

Topics: Administration, Topical; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Drug Design; Foot Dermatoses; Humans; Onychomycosis; United States; United States Food and Drug Administration

Systemic antifungal treatments are believed to be more effective than topicals for the treatment of onychomycosis; however, they are associated with more risks of adverse events. Tavaborole is the first member of a new class of antifungals that has been developed as a new topical nail solution for the treatment of toenail onychomycosis caused by dermatophytes. During Phase I-III clinical trials, tavaborole 5.0% nail solution showed a favorable safety and efficacy profile. Tavaborole 5.0% received US FDA market approval on 8 July 2014.

Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Evaluation; Foot Dermatoses; Humans; Microbial Sensitivity Tests; Onychomycosis

Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.

Topics: Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chemistry, Pharmaceutical; Ciclopirox; Diffusion; Diffusion Chambers, Culture; Drug Compounding; Ethanol; Hand Dermatoses; Humans; Molecular Structure; Nails; Onychomycosis; Permeability; Pharmaceutical Vehicles; Pilot Projects; Propylene Glycol; Pyridones; Solubility; Time Factors

A structure-activity relationship investigation for a more efficacious therapy to treat onychomycosis, a fungal infection of the toe and fingernails, led to the discovery of a boron-containing small molecule, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), which is currently in clinical trials for onychomycosis topical treatment.

Topics: Administration, Topical; Antifungal Agents; Aspergillus fumigatus; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Candida; Microbial Sensitivity Tests; Onychomycosis; Structure-Activity Relationship; Trichophyton