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A Closer Look At The Potential Of Topical Efinaconazole For Treating Onychomycosis In Pediatric Patients

Onychomycosis is a chronic fungal infection of the toenails and/or fingernails that has a global prevalence in children of 0.35 to 5.5 percent.1 Approximately 15 percent of all nail dystrophies in children are due to onychomycosis.2 Though less common in children than adults, toenail onychomycosis can result in permanent toenail discomfort and deformity.1,3 As the location of the infection is deep under the densely keratinized nail plate, treatment is difficult and can require prolonged use of systemic antifungals.4,5 

Currently, the only treatments for onychomycosis approved in the United States for patients under 18 years of age are the topical medications ciclopirox, tavaborole and efinaconazole.6-8 The efficacy of these treatments varies greatly and there is a lack of clinical data in pediatric populations. Accordingly, let us take a closer look at current onychomycosis treatments and the potential impact of topical efinaconazole for pediatric patients.

A Note On Comparing Treatment Efficacy Results From Clinical Trials

When reviewing results from clinical studies of onychomycosis treatments, it is important to note that in addition to differences in study designs, commonly used measures of treatment efficacy, such as mycological cure and complete cure, do not have standard definitions across studies.9 These issues can limit the accuracy of direct comparisons. Unless noted otherwise, the efficacy data I will discuss in this article utilizes negative potassium hydroxide (KOH) test and a negative fungal culture of the target great toenail sample as the definition of mycological cure. Complete cure will be defined as zero percent clinical involvement of the target toenail plus mycological cure.

Oral And Topical Treatments For Onychomycosis: What The Evidence Shows

Systemic (oral) antifungal treatments are traditionally the treatment of choice as they can effectively penetrate the nail bed and plate to reach the infection.5 The two treatments currently approved in the U.S. for adult use are once-daily terbinafine and once-daily itraconazole. Fluconazole is available off-label.9 

In a 12-week study of itraconazole for onychomycosis 54 percent of 110 adult patients achieved mycologic cure and 14 percent achieved complete cure.10 Cure rates were higher in a 48-week study of terbinafine (12 weeks treatment, 36 weeks follow-up) with 70 percent of adult patients achieving mycological cure and 38% achieving complete cure.11 While oral treatments are efficacious against onychomycosis, there are potential safety concerns such as drug-drug interactions and liver toxicity, especially with prolonged use.10-12 Currently there are no oral treatments for onychomycosis that are approved for use in children.

The three topical treatments for onychomycosis approved in the U.S. are once-daily ciclopirox 8%, tavaborole 5% and efinaconazole 10%.6-8 Topical treatments reduce systemic exposure, which may decrease the risk of drug-drug interactions and serious adverse events.1,12 The main limitations with topicals are limited nail bed penetration and the need for prolonged periods of use (greater than or equal to 12 months) due to the slow growth of toenails.4,5,9 

Ciclopirox, a synthetic antifungal, earned FDA approval in 1999, and tavaborole, an oxaborole antifungal, received FDA approval in 2014.6,7 Clinical trials of two studies each of ciclopirox (n=112 and 119; 48 weeks treatment) and tavaborole (n=399 and 396; 52 weeks treatment) in adults show mycological and complete cure rates ranging from 29 to 36 percent and 5.5 to 9.1 percent respectively.13,14 

Efinaconazole is an azole antifungal that was approved in 2014.8 In two 52-week studies (n=583 and 656), mycologic cure rates were 53.4% and 55.2%, and complete cure rates were 15.2% and 17.8% respectively.15 The higher mycologic cure rate observed with efinaconazole may be a result of its low binding to keratin in comparison with ciclopirox, its stronger fungicidal activity in the presence of nail keratin in comparison with tavaborole and ciclopirox, and greater nail permeability in comparison with ciclopirox.16,17 

Treatments For Pediatric Patients With Onychomycosis: What You Should Know 

As I noted earlier, there are currently no oral onychomycosis treatments approved in the U.S. for patients under 18 years of age. While one may prescribe oral treatments off-label, there are concerns about possible adverse events, especially in pediatric patients.12 Topical treatments may work best in children as their nails are faster growing, thinner and present a smaller surface area for infection than those of adults.18 In addition, treating the disease early (infection for less than one year) may improve cure rates and prevent the need for oral treatments further down the line.19 

The three topicals approved for onychomycosis treatment in adults are also approved for use in pediatric patients aged 12 years and older (ciclopirox in 1999) or six years and older (tavaborole in 2018, efinaconazole in 2020). 

In a 52-week, open-label, phase 4 study of tavaborole in 54 patients aged six to 16 years, mycologic and complete cure rates were 36.2 and 8.5 percent respectively, similar to rates in the 52-week adult tavaborole studies.14,20 Efficacy rates for efinaconazole in a similarly designed study in 60 patients aged six to 16 years were high with mycologic and complete cure rates of 65 and 40 percent respectively.21,22 These rates were greater than those observed in the two studies of efinaconazole in adults as well as the tavaborole pediatric study.15,20 Notably, in the pediatric efinaconazole study, the complete cure rate was more than twofold greater than the adult efinaconazole studies (40 percent versus 15 to 18 percent) and nearly fivefold greater than the pediatric tavaborole study (40 percent versus 8.5 percent).15,20 Finally, mycologic and complete cure rates from a 32-week study of topical ciclopirox in 35 patients aged two to 16 years were 77.1 and 34.2 percent.23

While the mycologic cure rate for ciclopirox was higher than that observed in the tavaborole and efinaconazole adult and pediatric studies discussed above, it is important to note that the cure definitions in the ciclopirox study were not as stringent (complete cure: subjective investigator’s Global Assessment scores (a standard in clinical research) and negative fungal culture; mycologic cure: negative fungal culture). 

When comparing the negative fungal culture rates in pediatric patients across the topical treatments, a greater percentage had negative cultures with efinaconazole (88.3 percent) versus tavaborole (87.2 percent) or ciclopirox (77.1 percent).20,21,23,24 Overall, efinaconazole 10% shows greater cure rates than tavaborole in a comparably designed study in pediatric patients. Furthermore, the evidence supports efinaconazole as being safe for pediatric patients with a favorable safety profile in the 52-week open-label study that was comparable with that from two, 52-week phase 3 efinaconazole studies in adults.15,21,22 

Concluding Thoughts

Onychomycosis treatment can be difficult and require long-term use of an oral or topical drug. Oral treatments are efficacious but require monitoring for potential safety issues such as liver toxicity. Topical treatments may reduce the risk of serious side effects and can be an attractive option for pediatric patients. Studies demonstrate that efinaconazole 10% topical solution is a highly efficacious and safe treatment for patients six years of age or older with toenail onychomycosis.

Dr. Vlahovic is a Clinical Professor in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine in Philadelphia. 

Disclosure: Dr. Vlahovic has served as an investigator and speaker for Ortho Dermatologics. The blog was supported by Ortho Dermatologics. Medical writing support was provided by Prescott Medical Communications Group (Chicago, IL) with financial support from Ortho Dermatologics, a division of Bausch Health US, LLC.

References

1. Gupta AK, Mays RR, Versteeg SG, et al. Onychomycosis in children: Safety and efficacy of antifungal agents. Pediatr Dermatol. 2018;35(5):552-559.

2. Rodriguez-Pazos L, Pereiro-Ferreiros MM, Pereiro M, Jr., Toribio J. Onychomycosis observed in children over a 20-year period. Mycoses. 2011;54(5):450-453.

3. Daniel RC. Onychomycosis: burden of disease and the role of topical antifungal treatment. J Drugs Dermatol. 2013;12(11):1263-1266.

4. Narasimha Murthy S, Wiskirchen DE, Bowers CP. Iontophoretic drug delivery across human nail. J Pharm Sci. 2007;96(2):305-311.

5. Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the emergence of newer agents. J Clin Aesthet Dermatol. 2014;7(7):10-18.

6. PENLAC® NAIL LACQUER (ciclopirox) topical solution 8%. US prescribing information. Bridgewater, NJ: Sanofi-Aventis US, LLC: 2006. 

7. KERYDIN® (tavaborole) topical solution 5%. US prescribing information. Melville, NY: PharmaDerm: 2018.  

8. JUBLIA® (efinaconazole) topical solution 10%. US prescribing information. Bridgewater, NJ: Bausch Health US, LLC: 2020.

9. Gupta AK, Stec N. Recent advances in therapies for onychomycosis and its management. F1000Res. 2019;8. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600855/ . Accessed July 20, 2020.

10. SPORANOX® (itraconazole) oral capsules. US prescribing information. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.: 2010.

11. LAMISIL® (terbinafine hydrchloride) oral tablets. US prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation: 2017.

12. Eichenfield LF, Friedlander SF. Pediatric onychomycosis: The emerging role of topical therapy. J Drugs Dermatol. 2017;16(2):105-109.

13. Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the treatment of onychomycosis of the toenails in the United States. J Am Podiatr Med Assoc. 2000;90(10):495-501.

14. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73(1):62-69.

15. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68(4):600-608.

16. Tachibana H, Kumagai N, Tatsumi Y. Fungicidal activity in the presence of keratin as an important factor contributing to in vivo efficacy: A comparison of efinaconazole, tavaborole, and ciclopirox. J Fungi (Basel). 2017;3(4).

17. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014;58(7):3837-3842.

18. Feldstein S, Totri C, Friedlander SF. Antifungal therapy for onychomycosis in children. Clin Dermatol. 2015;33(3):333-339.

19. Rich P. Efinaconazole topical solution, 10%: The benefits of treating onychomycosis early. J Drugs Dermatol. 2015;14(1):58-62.

20. Rich P, Spellman M, Purohit V, Zang C, Crook TJ. Tavaborole 5% topical solution for the treatment of toenail onychomycosis in pediatric patients: Results from a phase 4 open-label study. J Drugs Dermatol. 2019;18(2):190-195.

21. Eichenfield LF, Elewski BE, Sugarman JL, et al. Efinaconazole 10% topical solution for the treatment of onychomycosis in pediatric patients: Open-label phase 4 study. JAAD. 2020. In press. Available at: https://doi.org/10.1016/j.jaad.2020.06.1004 . Published July 1, 2020. Accessed July 20, 2020.

22. Eichenfield LF, Elewski B, Sugarman JL, Rosen T, Gupta A, Pillai R, Lin T. Safety, pharmacokinetics, and efficacy of efinaconazole 10% topical solution for the treatment of onychomycosis in pediatric patients. SKIN: The Journal of Cutaneous Medicine. 2020;4(1):S22. 

23. Friedlander SF, Chan YC, Chan YH, Eichenfield LF. Onychomycosis does not always require systemic treatment for cure: a trial using topical therapy. Pediatr Dermatol. 2013;30(3):316-322.

24. Data on file, Bausch Health Americas, Inc. Study V01-108A-401.

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