Transungual Delivery of Efinaconazole: Its Deposition in the Nail of Onychomycosis Patients and In Vitro Fungicidal Activity in Human Nails

November 2014 | Volume 13 | Issue 11 | Original Article | 1388 | Copyright © November 2014

Misao Sakamoto MS,a Noriaki Sugimoto MS,b Hideki Kawabata MS,a Eiko Yamakawa MS,a
Nobuyuki Kodera MS,a Radhakrishnan Pillai PhD,c and Yoshiyuki Tatsumi PhDd

aKaken Pharmaceutical Co Ltd, Tokyo, Japan
bKaken Pharmaceutical Co Ltd, Shizuoka, Japan
cDow Pharmaceutical Sciences, a division of Valeant Pharmaceuticals, Petaluma, CA
dKaken Pharmaceutical Co Ltd, Kyoto, Japan

Abstract
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.

J Drugs Dermatol. 2014;13(11)1388-1392.

INTRODUCTION

Onychomycosis is a chronic, progressive disease of the nails with high prevalence and burden of illness.1,2,3 Choice of therapy depends on type of onychomycosis, number of infected nails, nail thickness and severity of nail involvement.4 The number of agents available to treat the disease is limited mainly to oral drugs. There is a real medical need for an effective topical treatment where the medication is applied directly to the affected nails, thereby decreasing systemic exposure and the risk of adverse events (AEs) and drug-drug interactions commonly associated with oral onychomycosis drugs.
Efinaconazole is the first topical triazole developed specifically for the treatment of onychomycosis. It has a broad-spectrum of activity and has potent antifungal activity in vitro against the most common onychomycosis pathogens; T. rubrum and T. mentagrophytes (MIC90: 0.008 and 0.015 μg/mL, respectively) and C. albicans (MIC50: 0.004 μg/mL).5
Antifungal activity observed in vitro is not necessarily predictive of clinical outcome, although it is an important indicator of therapeutic success. Unfortunately, transungual delivery of effective topical treatments for onychomycosis has been limited by their low permeation rates through the dense keratinized nail plate to the site of infection in the deeper layers and the nail bed.6,7 In addition, some antifungal drugs are known to possess high affinity to keratin, a property that can have a deleterious effect on nail penetration and efficacy.8 Keratin binding can decrease drug penetration, even after repeated administration, and drug-bound to keratin is inactive. Efinaconazole exhibits lower binding to keratin, and the keratin-bound drug is released at a faster rate when compared to ciclopirox and amorolfine.8,9 This lower keratin affinity of efinaconazole reflected its greater amount permeated across nail plate than ciclopirox and amorolfine.9
Our studies aimed to determine the concentrations of efinaconazole in the toenails of onychomycosis patients treated with efinaconazole solution, and whether these were influenced by the presence of disease or nail thickness. In addition, we aimed to evaluate in vitro whether transungual delivery of