Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

Abstract

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...

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

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Development of terbinafine solid lipid nanoparticles as a topical delivery system

“…7,8 Moreover, the TB treatment duration is shorter in most cases. 9,10 Based on several clinical studies conducted in humans [11][12][13] and animals, 14,15 it was noted that TB accumulates in the skin and persists at high concentrations for up to several weeks after discontinuing drug application. The superior efficacy of TB after the end of the treatment period is attributed to its fungicidal effect in addition to the favorable pharmacokinetic characteristics of substantial and rapid penetration into the stratum corneum (SC), where it remains in the skin for a long time after discontinuing treatment.…”

Efeitos de doses elevadas da terbinafina e itraconazol em ratos Wistar

“…Kan e Bennet (1988) observaram que a terbinafina diluída em uma solução com 1% Tween 20 e 5% DMSO em água destilada resultou em maiores níveis plasmáticos do fármaco. Estudos têm demonstrado que a ação da terbinafina é dose-dependente, alcançando concentrações maiores no plasma quando administrada em doses elevadas (Hosseini-Yeganeh, McLachlan, 2002;Chapman et al, 2004). O efeito semelhante tem sido observado com o itraconazol, que, quando administrado em doses maiores, resulta no aumento das concentrações plasmáticas, ocorrendo, conseqüentemente, uma ação mais efetiva do fármaco.…”