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

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.

J Drugs Dermatol. 2013;12(9):1010-1016.


Onychomycosis is a common, chronic and recurring fungal infection of the toenails, and (less frequently) fingernails. The disease shows increasing incidence in the elderly, with almost 50% of adults over the age of 70 years being affected.1,2 It is not life-threatening; but should not be considered purely a cosmetic problem. Significant physical and psychological effects, such as pain and decreased self-esteem may occur.3
Current onychomycosis treatment strategies include both oral and topical antifungal agents,4 but the successful management of the disease can be challenging. An oral antifungal is the preferred first line therapy because of its superior efficacy and shorter treatment duration. However, their use is potentially limited by safety concerns, such as hepatotoxicity, and drug-drug interactions (DDIs). In treating individuals undergoing systemic polypharmacy for comorbid conditions like diabetes, peripheral vascular disease and immunosuppression (all prognostic factors for onychomycosis), DDIs are a concern especially in the elderly (where both onychomycosis and polypharmacy are common).5 DDIs can cause a substantial increase or decrease in exposure to a drug and/or its active metabolites, which in turn can alter its safety and efficacy profile.
Itraconazole and terbinafine are approved in the USA for oral treatment of onychomycosis. Both drugs, metabolized extensively in the liver, have the potential to alter the metabolism of concomitant medications and vice versa.
Itraconazole is a substrate and a potent inhibitor of CYP3A4. It can increase plasma concentrations of drugs metabolized by this enzyme, leading to potentially serious, life-threatening events.1 There are several drugs known to be affected on co-administration with itraconazole, or that affect the plasma levels