In an open pilot study, 12 children with tinea capitis were treated for 6 weeks with oral terbinafine (125 mg/day), and followed up 2 weeks later. The study was conducted to evaluate the efficacy, safety and pharmacokinetics of terbinafine. All patients were completely cured at the end of the treatment period, and there was no evidence of relapse at follow-up. Seven had a negative culture after 3 weeks of treatment. The time to obtain culture conversion from positive to negative did not appear to be related to body weight, but to clinical severity at baseline. Terbinafine is well tolerated and safe over a 56-day period. The kinetic data show a higher clearance of terbinafine in children compared with adults, with shorter alpha- and beta-phase elimination half-lives. However, a longer terminal gamma-phase (at least 6 days) is observed, as in adults, after multiple dose administration, and this is related to elimination from the tissues. The plasma concentrations are comparable between children and adults at a steady state (125 mg/day).
The plasma pharmacokinetics, and the urinary excretion, of terbinafine and its five main metabolites have been investigated after a single oral dose administration of 125 mg to 16 healthy subjects. In plasma, the highest concentrations are observed for the two carboxybutyl metabolites, with a predominance for the carboxybutylterbinafine. For this metabolite, as compared to terbinafine, the Cmax and AUC are 2.4 and 13 times higher respectively. The demethylterbinafine presents a plasma profile close to that of terbinafine. The two hydroxy metabolites are only found as glucuronide and are of minor importance. The apparent terminal half-lives of terbinafine, demethylterbinafine, and the two carboxy metabolites appear to be similar (approximately 25 h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of 14C-terbinafine, the parent drug and these five metabolites, account for more than 80% of the total radioactivity in plasma over the 0-48 h interval following administration. In urine, the major metabolite is demethylcarboxybutylterbinafine, which amounted to about 10% of the administered dose. Terbinafine and demethylterbinafine are only excreted as trace amounts in urine. Carboxybutylterbinafine and the two hydroxy metabolites are excreted in the range of 0.5-2% either as glucuronides or free. Urinary excretion over the 0-48 h interval of terbinafine and of the five metabolites amounted to about 14% of the administered dose. This is far below the level of total radioactivity measured in urine over the same interval (approximately 57%), after administration of 14C-terbinafine. This shows in contrast to plasma, that numerous other metabolites are present in urine.
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
In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.
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