Safety and Pharmacokinetics of Efinaconazole 10% Solution in Healthy Volunteers and Patients With Severe Onychomycosis: Low Systemic Exposure Suggests Remote Drug-Drug Interaction Potential
September 2013 | Volume 12 | Issue 9 | Original Article | 1010 | Copyright © September 2013
Michael Jarratt MD,a William Jo Siu PhD DABT,b Eiko Yamakawa MS,c
Nobuyuki Kodera MS,c Radhakrishnan Pillai PhD,b and Kathleen Smith MBAb
aDermResearch, Inc., Austin, TX
bDow Pharmaceutical Sciences Inc. a Division of Valeant Pharmaceuticals North America, LLC, Petaluma, CA
cKaken Pharmaceutical Co., Ltd., Tokyo, Japan
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.
J Drugs Dermatol. 2013;12(9):1010-1016.