In Vitro Nail Penetration and Antifungal Activity of Tavaborole, a Boron-Based Pharmaceutical

June 2015 | Volume 14 | Issue 6 | Original Article | 609 | Copyright © June 2015


Dina Coronado BS, Tejal Merchant MPharm, Sanjay Chanda PhD, and Lee T. Zane MD

Anacor Pharmaceuticals, Inc., Palo Alto, CA

Abstract
An effective topical antifungal medication must penetrate through the nail plate at sufficient concentrations to eradicate the fungal infection. Tavaborole topical solution, 5% is a novel boron-based pharmaceutical approved for the treatment of toenail onychomycosis due to Trichophyton rubrum or T mentagrophytes. Four in vitro studies assessed the antifungal activity and nail penetration of tavaborole. In Study 1, tavaborole demonstrated minimum inhibitory concentration (MIC) values ranging from 0.25–2 μg/mL against all fungi tested; addition of 5% keratin powder did not affect the MIC against T rubrum. The minimum fungicidal concentration (MFC) values for tavaborole against T rubrum and T mentagrophytes were 8 and 16 μg/mL, respectively. In Study 2, tavaborole effectively penetrated through the nail plate; mean concentrations in the ventral/intermediate nail layer were significantly higher than ciclopirox at day 15. In Study 3, mean cumulative tavaborole penetration through ex vivo human nails was significantly higher than ciclopirox at day 15. In Study 4, tavaborole demonstrated superior nail penetration and fungicidal activity, as measured by zones of inhibition. These studies demonstrated the superior penetration of tavaborole through the nail plate vs ciclopirox. Tavaborole demonstrated robust antifungal activity, with low MIC and MFC values, even in the presence of keratin.

J Drugs Dermatol. 2015;14(6):609-614.

INTRODUCTION

Onychomycosis is a fungal infection of the nail unit caused by dermatophytes in the majority of patients.1,2 Two primary types of Trichophyton involved in this disease are T rubrum and T mentagrophytes (also known as T interdigitale) 3; in patients with onychomycosis, these fungi reside in the nail bed under the nail plate.1 The clinical presentation of toenail onychomycosis includes discoloration and streaking of the nail plate, subungual hyperkeratosis, and nail plate thickening.4,5 If left untreated, the fungal infection can worsen, resulting in substantial discomfort, pain, difficulty with wearing shoes and walking, and substantially reduced quality of life.2,6-9
Guidelines for the treatment of onychomycosis recommend oral and topical antifungal agents as effective therapies.10-12 Oral antifungal agents (eg, terbinafine and itraconazole) are considered to be the most effective treatment options for onychomycosis because they can effectively reach the nail bed through systemic circulation.13 However, limitations of these agents include drug–drug interactions with agents that are metabolized by specific cytochrome P450 (CYP) enzymes, potential inhibition of certain CYP subtypes, and adverse effects such as hepatotoxicity and congestive heart failure.13-15 The prescribing information for itraconazole contains boxed warnings of rare cases of serious hepatotoxicity with treatment (including liver failure and death, even in patients with no pre-existing liver disease or serious underlying medical condition) as well as congestive heart failure, due to the appearance of negative inotropic effects seen in healthy volunteers and animals administered intravenous itraconazole.15
Topical antifungal agents are not associated with risk of drug–drug interactions or systemic toxicity. However, some topical agents are limited by relatively low efficacy due to their inability to effectively penetrate through the nail plate at sufficient concentrations to eradicate the fungal infection13,16 and require routine debridement in conjunction with topical treatment.17 Multiple factors can affect penetration of topical antifungal agents, including properties of the drug molecule (eg, size, shape, ionic charge, hydrophilicity), characteristics of the drug formulation (eg, nature of vehicle, pH, drug concentration), and properties of the nail (eg, hydration, disease state).18,19 Of these, the most critical factor influencing penetration is the molecular weight of the drug.19 Molecular size has an inverse relationship with penetration through the nail plate; a smaller molecule passes more easily through the dense keratin fibers of the nail.16 Hydrophilicity is also considered an important factor for an antifungal agent to successfully penetrate through the nail plate and into the nail bed.19
Kerydin® ([tavaborole] topical solution, 5%; Anacor Pharmaceuticals, Inc, Palo Alto, CA) is a novel, boron-based pharmaceutical approved by the United States Food and Drug
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