Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis

Evans, E. G. V.; Sigurgeirsson, Bárður

doi:10.1136/bmj.318.7190.1031

Cited by 241 publications

(175 citation statements)

References 15 publications

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“…Further, the therapeutic efficacy of efinaconazole has been established in mild to moderate DLSO patients in two phase III clinical trials (16). Its mycological cure rate is comparable to that reported with oral itraconazole, and the complete cure rate is 2-to 3-fold higher than that of ciclopirox nail lacquer (17,18).…”

mentioning

confidence: 70%

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Sugiura

Sugimoto

Hosaka

et al. 2014

Antimicrob Agents Chemother

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Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

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confidence: 70%

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Sugiura

Sugimoto

Hosaka

et al. 2014

Antimicrob Agents Chemother

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“…The lipophilic and keratophilic nature of terbinafine leads to the accumulation of this drug in adipose and keratinous tissues such as nail, hair, and particularly skin. These characteristics of terbinafine make it the drug of first choice in the treatment of dermatophytosis and onychomycosis (11,17). Furthermore, it has been shown that systemic treatment with terbinafine is more efficient than topical administration in the treatment of onychomycosis (41).…”

Section: Discussionmentioning

confidence: 99%

“…It has demonstrated activity against most superficial fungal infections, including onychomycosis and dermatomycosis (11,17), and systemic fungal infections, such as histoplasmosis (1), Pneumocystis carinii infection, (8), and aspergillosis (39). Terbinafine is highly lipophilic and keratophilic, so it is extensively distributed throughout adipose tissue, dermis, epidermis, and nails in humans (12,19).…”

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confidence: 99%

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

Hosseini-Yeganeh

McLachlan

2002

Antimicrob Agents Chemother

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The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n ‫؍‬ 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (V ss ) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the V ss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.Terbinafine is an antifungal agent from the allylamine class that inhibits the fungal squalene epoxidase enzyme, leading to the intracellular accumulation of squalene, which causes the rapid death of fungi (36,37). It has demonstrated activity against most superficial fungal infections, including onychomycosis and dermatomycosis (11,17), and systemic fungal infections, such as histoplasmosis (1), Pneumocystis carinii infection, (8), and aspergillosis (39). Terbinafine is highly lipophilic and keratophilic, so it is extensively distributed throughout adipose tissue, dermis, epidermis, and nails in humans (12,19). The apparent volume of distribution in humans is relatively large and has been reported to be in the range of 780 to 2,000 liters (22,25,27,28,33). The large volume of distribution of terbinafine and its accumulation in peripheral tissue as well as the slow redistribution of the drug into blood are likely to significantly influence the half-life of terbinafine. Previous studies have variously reported the elimination half-life of terbinafine in humans to be 15 h (33), 26 h (27), 290 h (35), and 22 days (33,35,43). Terbinafine is extensively metabolize...

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“…Terbinafine has a broad spectrum and is considered a fungicidal in vitro whereas the azoles (e.g. ; ketoconazole) are primarily fungistatic and this may partially account for the greater efficacy of terbinafine [30] .…”

Section: Discussionmentioning

confidence: 99%

Bacterial and fungal endophthalmitis in Upper Egypt: related species and risk factors

Gharamah

Moharram

Ismail

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

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Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis

Cited by 241 publications

References 15 publications

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

Bacterial and fungal endophthalmitis in Upper Egypt: related species and risk factors

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