In Vitro Human Onychopharmacokinetic and Pharmacodynamic Analyses of ME1111, a New Topical Agent for Onychomycosis

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 1
• Main Authors: Kubota-Ishida, Natsuki, Takei-Masuda, Naomi, Kaneda, Kaori, Nagira, Yu, Chikada, Tsubasa, Nomoto, Masahiro, Tabata, Yuji, Takahata, Sho, Maebashi, Kazunori, Hui, Xiaoying, Maibach, Howard I
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.01.2018
• Subjects: Antifungal Agents; Nails; Onychomycosis; Pharmacology; Phenols; Pyrazoles; ME1111; topical agent; onychomycosis; dermatophyte; nail permeability
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00779-17

ME1111 is a novel antifungal agent currently under clinical development as a topical onychomycosis treatment. A major challenge in the application of topical onychomycotics is penetration and dissemination of antifungal agent into the infected nail plate and bed. In this study, pharmacokinetic/pharmacodynamic parameters of ME1111 that potentially correlate with clinical efficacy were compared with those of marketed topical onychomycosis antifungal agents: efinaconazole, tavaborole, ciclopirox, and amorolfine. An ME1111 solution and other launched topical formulations were applied to an dose model for 14 days based on their clinical dose and administration. Drug concentrations in the deep layer of the nail and within the cotton pads beneath the nails were measured using liquid chromatography-tandem mass spectrometry. Concentrations of ME1111 in the nail and cotton pads were much higher than those of efinaconazole, ciclopirox, and amorolfine. Free drug concentrations of ME1111 in deep nail layers and cotton pads were orders of magnitude higher than the MIC value against ( = 30). Unlike other drugs, the antifungal activity of ME1111 was not affected by 5% human keratin and under a mild acidic condition (pH 5.0). The antidermatophytic efficacy coefficients (ratio of free drug concentration to MIC s against ) of ME1111, as measured in deep nail layers, were significantly higher than those of efinaconazole, tavaborole, ciclopirox, and amorolfine ( < 0.05). This suggests that ME1111 has excellent permeation of human nails and, consequently, the potential to be an effective topical onychomycosis treatment.