Elimination Kinetics of Terbinafine from Human Plasma and Tissues following Multiple-Dose Administration, and Comparison with 3 Main Metabolites

Abstract

SummaryTrough and peak concentrations as well as the elimination kinetics of the antimycotic agent terbinafine and 3 metabolites were investigated following multiple-dose administration of terbinafine 250mg daily for 4, 12 and 48 weeks. Plasma, sebum and tissues such as the stratum corneum, dermis-epidermis, hair and nails were analysed. The elimination of all compounds was multiphasic, being faster initially. Mean terminal elimination half-lives of the parent drug determined in plasma and tissues ranged from 18 to 28 days, and were in the same range as those of the metabolites (21 to 28 days). The slowest terminal elimination of terbinafine was observed from the dermis-epidermis and from keratinic tissues like hair and nails. Trough plasma concentrations of terbinafine were highly consistent in all studies, indicating an accumulation (12.6-to 18.5-fold) after multiple-dose treatment. However, peak concentrations of terbinafine accumulated only slightly (1.3-fold).In plasma, the kinetics of the metabolites were similar with regard to their terminal elimination half-life. Like the parent drug, trough concentrations of the N-demethylated metabolite accumulated (8-to 12.9-fold) after multiple-dose administration, but the peak concentrations did not. In contrast, the 2 carboxy metabolites accumulated only slightly (1.6-to 2.7-fold) under the same conditions.Terbinafine is a synthetic antimycotic agent of the allylamine class.[l] The compound is highly active against dermatophytes such as Trichophyton spp., Microsporum spp. and Epidermophyton floccosum, with minimal inhibitory concentrations (MICs) ranging from 1.5 to 10 Ilg/L in vitro [2,3,4] based on its interference with ergosterol biosynthesis, especially by the inhibition of the fungal squalene epoxidase)5] Terbinafine is readily absorbed by humans following oral administration,l6] with peak plasma concentrations ranging from 0.8 to 1.5 mg/L being

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

“…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. Only in subsequent multiple-dose investigations in which plasma washout kinetics were followed was a third disposition phase with a half-life of about 20 to 28 days clearly identifiable (4,13). The average t 1/2 of 17 days in the present investigation is in line with these results.…”

“…The average t 1/2 of 17 days in the present investigation is in line with these results. It is likely that this disposition phase is governed by the slow return of terbinafine to the central plasma compartment from peripheral tissue and adipose distribution sites (13).…”

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

“…The slow redistribution of terbinafine from tissues is responsible for the long elimination half-life observed for this drug. Based on these pharmacokinetic characteristics, terbinafine can be expected to provide sustained protection from a relapse of fungal infections following therapy (26); these pharmacokinetic characteristics also provide a rationale for a potentially shorter treatment time (13,28,43), which may be more convenient for patients.…”

“…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).…”

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

“…However, no studies have assessed the systemic exposure of higher-dose terbinafine treatment (Ͼ250 mg daily) or divided daily doses (every 12 h [q12h] or q8h), factors that are likely to be crucial to the utility of terbinafine in effectively treating systemic mycoses in combination with other antifungals. This paucity of pharmacokinetic data is particularly important for terbinafine due to its very long terminal elimination half-life (2 to 3 weeks [13]) and substantial accumulation in plasma over time; trough terbinafine concentrations following 250 mg once daily are known to accumulate Ͼ10-fold over 12 to 20 weeks (14), with the majority of the accumulation occurring in the first 4 weeks of therapy (13).…”