Safety and Tolerability of Luliconazole Solution 10-Percent in Patients with Moderate to Severe Distal Subungual Onychomycosis

The study objective was to evaluate the safety, tolerability, systemic exposure, and pharmacokinetics (PK) of 10% luliconazole solution (luliconazole) when topically applied once daily to all 10 toenails and periungual areas in patients with moderate to severe distal subungual onychomycosis. In this single-center, open-label study, 24 patients applied 20 mg/ml of luliconazole (twice the clinical dose) for 29 days with a 7-day follow-up. Complete PK profiles were determined on days 1, 8, 15, and 29. Safety/tolerability assessments included application site reactions, adverse events, vital signs, clinical laboratory findings, and electrocardiograms. Mean luliconazole plasma concentrations remained around the lower limit of quantitation (0.05 ng/ml) and were comparable on days 8, 15, and 29 (range, 0.063 to 0.090 ng/ml), suggesting steady state occurred by day 8. Every patient had undetectable plasma luliconazole levels for at least 11% of the time points, and 12 of the 24 patients had undetectable levels for at least 70% of the time points. The maximum plasma concentration of luliconazole (C(max)) observed in any patient was 0.314 ng/ml and the maximum area under the concentration-time curve from 0 to 24 h (AUC0-24) was 4.34 ng · h/ml. Five patients (21%) had measureable luliconazole levels in the plasma 7 days after the last dose. The median concentration of luliconazole in the nail at this time point was 34.65 mg/g (from 42 of 48 collected toenail samples). There was one mild incidence of skin erythema on day 5 that resolved on day 8, there were no reports of drug-induced systemic side effects, and there was no evidence of QT prolongation. Luliconazole, when applied once daily to all 10 fungus-infected toenails for 29 days, is generally safe and well tolerated and results in significant accumulation of drug in the nail. Systemic exposure is very low, with no evidence of drug accumulation.