Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment

- Efinaconazole administered dermally to mice, rats and minipigs was well tolerated.
- Reversible mild skin irritation after efinaconazole and vehicle dermal treatment.
- Target organ of systemic toxicity was liver (vacuolation) in rats dosed dermally.
- Efinaconazole was not carcinogenic in a 2-year mouse dermal study and not genotoxic.
- Low/moderate toxicity and high safety margins for topical onychomycosis therapy.

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 (13 weeks), rats (6 months) and minipigs (9 months) 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 50 mg/kg/day. No systemic toxicity was observed in mice and minipigs, at approximate high dermal doses of 930 and 170 mg/kg/day, respectively. Daily subcutaneous injection of propylene glycol vehicle or efinaconazole to rats for 6 months 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 40 mg/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.