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

Abstract

The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl-carboxybutyl form) in plasma were characterized for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 ؎ 0.77 g/ml occurring 1.2 ؎ 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal disposition half-life of 16.5 ؎ 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047, respectively. Nonrenal elimination constituted the major route of clearance for terbinafine and all three metabolites, with renal elimination playing a minor additional role in the clearance of metabolite SDZ 280-047. Measurable concentrations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.

In Vitro Activities of Terbinafine in Combination with Fluconazole, Itraconazole, Voriconazole, and Posaconazole against Clinical Isolates of Candida glabrata with Decreased Susceptibility to Azoles

“…Our in vitro results confirmed a limited activity of TRB when used alone, having a GM MIC of Ͼ8 g/ml. These MICs are severalfold higher than the achievable TRB levels in serum (6). On the other hand, our data indicate a clear enhancement of the in vitro activity of the allylamine when combined with the triazoles, decreasing the MICs to levels achievable in serum (58% of the isolates when combined with ITRA, 71% when combined with VRC, and 62% when combined with PSZ).…”

Synergistic Activities of Fluconazole and Voriconazole with Terbinafine against Four Candida Species Determined by Checkerboard, Time-Kill, and Etest Methods

“…However, by the time-kill method, the interaction was indifferent. The lowest FIC indices for the combination of both azoles and TRB were obtained at achievable concentrations in serum of 3.6 g/ml for TRB (3,11,18), 30 g/ml for FLC (9,17,18), and up to 5.2 g/ml for VRC (2,10,16). The three methods showed good correlation for most of the species, although by the checkerboard method, the synergistic effect was stronger.…”

In Vitro Activities of Terbinafine against Aspergillus Species in Comparison with Those of Itraconazole and Amphotericin B

“…Firstly, A. fumigatus accounts for around 90% of human infections (8), secondly, treatment is very often commenced without positive cultures. In addition, our MICs for A. fumigatus were higher than levels achievable in blood, since peak concentrations in plasma of ϳ1.7 g/ml are typically seen within 1.5 h of an oral 250-mg dose (7). No intravenous preparation is available.…”