title: Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment.
abstract: 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.
authors.affiliation: Dow Pharmaceutical Sciences, A Division of Valeant Pharmaceuticals International, 1330 Redwood Way, Petaluma, CA 94954, USA. Electronic address: wjo@dowpharmsci.com.
authors.forename: William
authors.initials: W
authors.lastname: Jo
authors.affiliation: Dow Pharmaceutical Sciences, A Division of Valeant Pharmaceuticals International, 1330 Redwood Way, Petaluma, CA 94954, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Glynn
authors.affiliation: Kaken Pharmaceutical Co., Ltd., 301, Gensuke, Fujieda, Shizuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nejishima
authors.affiliation: Kaken Pharmaceutical Co., Ltd., 301, Gensuke, Fujieda, Shizuoka, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Sanada
authors.affiliation: Kaken Pharmaceutical Co., Ltd., 301, Gensuke, Fujieda, Shizuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Minowa
authors.affiliation: Dow Pharmaceutical Sciences, A Division of Valeant Pharmaceuticals International, 1330 Redwood Way, Petaluma, CA 94954, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Calvarese
authors.affiliation: Kaken Pharmaceutical Co., Ltd., 301, Gensuke, Fujieda, Shizuoka, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Senda
authors.affiliation: Dow Pharmaceutical Sciences, A Division of Valeant Pharmaceuticals International, 1330 Redwood Way, Petaluma, CA 94954, USA.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Pillai
authors.affiliation: Dow Pharmaceutical Sciences, A Division of Valeant Pharmaceuticals International, 1330 Redwood Way, Petaluma, CA 94954, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Mutter
mesh_terms: D000279:Administration, Cutaneous; D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019055:No-Observed-Adverse-Effect Level; D014009:Onychomycosis / Q000188:drug therapy*; D019999:Pharmaceutical Solutions; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects*; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D019999:Pharmaceutical Solutions; D014230:Triazoles; C431707:efinaconazole
keywords: Antifungal; Efinaconazole; Onychomycosis; Safety assessment; Toxicity