Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails.

BACKGROUND: Effective transungual delivery of topical antifungal agents in onychomycosis has been hampered by poor nail permeation. To be effective they must have antifungal efficacy, and effectively permeate through the dense keratinized nail plate to the site of infection in the nail bed and nail matrix. The therapeutic efficacy of efinaconazole topical solution, 10% has been established in two phase 3 clinical trials in distal lateral subungual onychomycosis. OBJECTIVE: To investigate the transungual delivery of efinaconazole in onychomycosis patients and its fungicidal activity in the toenail. METHODS: Concentrations of efinaconazole were determined as part of a multi-center, open label study in forty onychomycosis patients following repeated application of efinaconazole topical solution, 5% and 10% to the toenails over 28 days, with a 2-week follow-up. Fungicidal activity against T. rubrum in the ventral layer of human nails was determined using an in vitro human nail infection model (ChubTur®). RESULTS: Efinaconazole concentrations in the nail were four orders of magnitude higher than MIC values of efinaconazole against dermatophytes. Further, nail drug concentrations were not influenced by the presence of disease or nail thickness, and maintained at high antifungal levels post-treatment. Efinaconazole was effective in reducing fungal viability, suggesting that sufficient amounts of efinaconazole were being delivered into the ventral layer of the nail plate.
CONCLUSIONS: Effective transungual delivery of efinaconazole was demonstrated. The high efinaconazole concentrations in patient toenails and fungicidal activity in vitro potentially contribute to the clinical efficacy reported in phase 3 studies.

Safety and pharmacokinetics of efinaconazole 10% solution in healthy volunteers and patients with severe onychomycosis.

OBJECTIVES: To characterize the systemic exposure and pharmacokinetics of efinaconazole 10% solution and assess the potential for drug-drug interaction (DDI) in human volunteers and onychomycosis patients following topical administration. METHODS: Two single-center, open-label studies in healthy volunteers and severe onychomycosis patients. Efinaconazole 10% solution was applied topically to all 10 toenails (0.42 mL total daily dose volume); administered as single and then 7 daily doses to 10 healthy volunteers, and once daily for 28 days to 19 severe onychomycosis patients. Plasma concentrations of efinaconazole and its major metabolite H3 were determined by LC-MS-MS at multiple timepoints. Safety evaluations were carried out throughout both studies. RESULTS: The mean peak plasma concentrations (Cmax) of efinaconazole and H3 were 0.54 and 1.63 ng/mL, respectively, in healthy volunteers; and 0.67 and 2.36 ng/mL, respectively, in patients. Both parent drug and metabolite accumulated following repeat dosing, and reached steady state in plasma by 14 days. Efinaconazole was well tolerated in both studies; no drug-related adverse events were reported. CONCLUSIONS: Efinaconazole 10% solution resulted in very low systemic exposures to efinaconazole and H3 when applied topically at maximum use conditions to healthy volunteer and onychomycosis patients' toenails. Efinaconazole is a CYP inhibitor like other azole antifungals, and its lowest ki is 91 ng/mL for CYP2C9, a >130-fold higher concentration than the mean steady state Cmax observed in patients. The Cmax/ki ratio was 0.007, well below the threshold for clinical DDI evaluation as recommended in regulatory guidances, thereby suggesting efinaconazole 10% solution has remote potential for drug-drug interactions.