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

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.