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.
Kovarik
J M
JM
Department of Human Pharmacology, Sandoz Pharma Ltd, Basel, Switzerland.
Kirkesseli
S
S
Humbert
H
H
Grass
P
P
Kutz
K
K
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D000077291:Terbinafine
D000935:Antifungal Agents; D009281:Naphthalenes; C073388:SF 86-621; D000077291:Terbinafine