Dose-proportional pharmacokinetics of terbinafine and its N-demethylated metabolite in healthy volunteers

Abstract

The dose-dependency of the pharmacokinetic parameters of terbinafine and its N-demethyl derivative was investigated in a randomized four-way crossover study in healthy volunteers following single oral administrations of 125, 250, 500 and 750 mg of terbinafine. Plasma concentrations of terbinafine and its metabolite were measured by a validated high-performance liquid chromatography (HPLC) method using ultraviolet detection. Concentration data were fitted to a two-compartment model. The relationship between Cmax or the area under the concentration curve (AUC) and the terbinafine dose was analysed by classical linear regression. Terbinafine disposition parameters were dose-independent, with the exception of Tmax and t1/2 alpha, which were prolonged with the 500- and 750-mg doses. The terbinafine Cmax and AUC, however, were linear and dose-proportional over the entire dose range. The N-demethylated metabolite appeared in plasma at the same time as terbinafine and showed similar prolongations in Tmax and t1/2 alpha with the 500- and 750-mg doses. In addition, the Cmax deviated from proportionality at these doses, giving values 22% lower than projected, while the AUC was linear and dose-proportional over the whole range of doses. The slight disproportionality in the dispositions of terbinafine and its N-demethyl metabolite at 500 and 750 mg are not expected to be clinically significant.

Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites

“…The single-dose plasma pharmacokinetics of terbinafine in this investigation were in good agreement with those of earlier studies in which rapid absorption and a biphasic decline in concentrations with a presumed t 1/2 of about 25 h were reported (1,8,9). Because of the limited duration of blood sampling and the assay limit of quantification, a third disposition phase was not observed in these early single-dose studies.…”

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

“…The pharmacokinetic data for terbinafine in human tissues, including the concentration-time profiles of terbinafine in plasma and skin tissue, were reconstructed from the graphical concentration-time data reported by Kovarik et al (27), Nedelman et al (32), and Faergemann et al (13) and by using the method described by Mayersohn and Tannenbaum (31) for recovering data from the literature. Only those studies with a selective and validated HPLC assay were selected.…”

“…In those studies, single or multiple oral doses of terbinafine were administered to healthy subjects. In a single-dose study (27), different doses of terbinafine (125, 250, 500, and 750 mg) were administered and blood samples were collected up to 48 h after terbinafine administration. In the multiple-dose studies reported by Faergemann et al (13) and Nedelman et al (32), 250 mg of terbinafine was administered to healthy subjects once daily for 14 days.…”

“…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.…”

“…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 metabolized in the liver by oxidation or N demethylation of the three carbon atoms bound to the central nitrogen atom or of the nitrogen atom itself (2), and the metabolites lack the antimycotic activity of the parent drug (34).…”