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: William Jo, Marian Glynn, Hiroaki Nejishima, Hisakazu Sanada, Kenji Minowa, Barry Calvarese, Hisato Senda, Radhakrishnan Pillai, Linda Mutter
• Journal: Regulatory toxicology and pharmacology : RTP (Regul Toxicol Pharmacol) Vol. 70 Issue 1 Pg. 242-53 (Oct 2014) ISSN: 1096-0295 [Electronic] Netherlands
• PMID: 25038564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antifungal Agents
• Pharmaceutical Solutions
• Triazoles
• efinaconazole

Topics

• Administration, Cutaneous
• Administration, Topical
• Animals
• Antifungal Agents (administration & dosage, toxicity)
• Dose-Response Relationship, Drug
• Female
• Injections, Subcutaneous
• Male
• Mice
• Mice, Inbred ICR
• No-Observed-Adverse-Effect Level
• Onychomycosis (drug therapy)
• Pharmaceutical Solutions
• Rats
• Rats, Sprague-Dawley
• Skin (drug effects)
• Swine
• Swine, Miniature
• Time Factors
• Triazoles (administration & dosage, toxicity)