Topical Antifungals for Onychomycosis: In Vitro Antifungal Activity, Ex Vivo Nail Penetration, and Clinical Efficacy

Background: Topical treatment of toenail onychomycosis may be preferred for patients for whom systemic adverse events, drug-drug interactions, and contraindications associated with oral antifungals are of concern. Three topical antifungals have been approved by the US Food and Drug Administration (FDA) for the treatment of toenail onychomycosis: ciclopirox 8% lacquer, efinaconazole 10% solution, and tavaborole 5% solution. In the absence of head-to-head clinical trials, the objective of this review is to compare in vitro antifungal activity, ex vivo human nail penetration, and clinical efficacy of these topical onychomycosis treatments. Methods: In vitro antifungal activity, defined as the minimum concentration of drug needed to inhibit 90% of fungal growth (MIC90), was assessed for each antifungal against Trichophyton rubrum and T. mentagrophytes, the most common causative fungi in onychomycosis (lower MIC=greater antifungal activity). To assess nail penetration, each antifungal was applied to a human cadaverous toenail; disks punched from the coated nails were placed onto agar plates seeded with clinical isolates of each fungal species. After incubation, antifungal activity was measured as the radius of the area of no fungal growth (zone of inhibition; ZI). Clinical efficacy data were gathered from prescribing information and/or publications of pivotal phase 3 clinical trials, in which each drug was applied daily for 48 weeks (plus debridement with ciclopirox). Outcomes were mycologic cure (negative fungal culture and negative KOH staining), complete/almost complete cure (mycologic cure and ≤5-10% target nail involvement), and complete cure (mycologic cure and 0% target nail involvement). Results: Efinaconazole demonstrated the greatest in vitro antifungal activity against both Trichophyton species. MIC90 values for efinaconazole ranged from 0.008-0.125 mg/mL, compared with 0.25-0.5 mg/mL for ciclopirox and 8 mg/mL for tavaborole. In the ex vivo nail penetration assay, ZIs for efinaconazole (T. rubrum: 82.1 mm; T. mentagrophytes: 63.8 mm) were significantly greater than for ciclopirox and tavaborole (7.4-63.5 mm and 3.6-39.1 mm, respectively; P<0.001, all). Accordingly, efinaconazole demonstrated greater clinical efficacy, with higher rates of mycological cure (53.4-55.2% vs 29.0-36.0% for ciclopirox and tavaborole), complete/almost complete cure (23.4-26.4% vs 6.5-17.9%), and complete cure (15.2-17.8% vs 5.5-9.1%). Conclusions: Among FDA-approved topical therapies approved for the treatment of toenail onychomycosis, efinaconazole 10% solution demonstrated the greatest in vitro antifungal activity, human nail penetration, and clinical efficacy. Funding: Ortho Dermatologics.