Safe coadministration of terbinafine and terfenadine: A placebo-controlled crossover study of pharmacokinetic and pharmacodynamic interactions in healthy volunteers

Abstract

The pharmacokinetic and pharmacodynamic interactions of terbinafine (Lamisil) and terfenadine (Seldane) were assessed in 26 healthy volunteers randomized to receive either terbinafine (250 mg tablet) or its placebo (terbinafine placebo), which were administered in a double-blind manner once daily for 18 days. On days 12 through 18, terfenadine was coadministered (60 mg twice daily, unblinded). Pharmacokinetic profiles were obtained for terbinafine and its desmethyl metabolite on day 11 (in the absence of terfenadine), day 12, and day 18. Terfenadine and terfenadine acid metabolite levels were also assayed on days 12 and 18. After a 4-week washout period, subjects were crossed over to the alternate treatment (terbinafine or terbinafine placebo). Pharmacodynamic measures were electrocardiographic (ECG) rhythm abnormalities, corrected QT interval (QTc), and plasma ALT levels. Terfenadine levels were evaluated; however, only eight of 1502 samples assayed were above the limit of quantitation. No effect of terbinafine administration on pharmacokinetic parameters for the terfenadine acid metabolite was observed, except for a decrease of approximately 20% in through terbinafine concentrations (C0hr; p < 0.05) on the last day of terfenadine plus terbinafine coadministration. Pharmacokinetic parameters for terbinafine were unchanged on the first day of terfenadine coadministration, and only small increases in area under the plasma concentration versus time curve from 0 to 24 hours and peak plasma concentrations (16.1%[p < 0.01] and 6.63% [p < 0.05]) were observed on the last day of terfenadine and terbinafine coadministration. Values for C0hr were also about 20% to 25% higher (p < 0.05). Steady-state levels of the terfenadine acid metabolite were achieved after 2 days of terfenadine coadministration, and steady-state levels of terbinafine and its desmethyl metabolite were achieved after 14 days of terbinafine administration. The incidence of ECG rhythm abnormalities was not significantly higher in any treatment group; however, the incidence of prolongation of QTc > 10% above baseline was significantly higher in the groups treated with terfenadine. No QTc prolongation occurred in the absence of terfenadine treatment. Both terbinafine and terfenadine were well tolerated when coadministered during this study, as indicated by the low incidence of complaints, abnormalities, and adverse events. The results of this study indicate that terbinafine and terfenadine can be safely coadministered.

Pharmacokinetics of Orally Administered Terbinafine in African Penguins (Spheniscus demersus) for Potential Treatment of Aspergillosis

“…5 Human serum terbinafine concentration time profiles, based on single oral doses of 250 mg in humans, are similar but of shorter duration, with an initial elimination t K of 22 hr and a final elimination t K of just under 4 days. 39 In multiple dose studies conducted in humans, terbinafine distribution and elimination are similar to that seen after single dose administration, with the t K variously reported as 165 6 49 hr, 51 293 6 165 hr, 64 16 6 2.8 days, 30 and up to 3 wk. 50,85 The clearance rate of terbinafine in plasma can also be affected by other drugs.…”

Evaluation of 170 Xenobiotics as Transactivators of Human Pregnane X Receptor (hPXR) and Correlation to Known CYP3A4 Drug Interactions

“…Terbinafine (250 mg QD for 7 days) resulted in a 15% decrease in C max and AUC concentrations of cyclosporine, although the change was not considered clinically significant and no dose adjustments for cyclosporine were indicated [67]. Also, terbinafine (250 mg QD for 18 days) resulted in a 20% decrease in trough terfenadine concentrations, yet no significant changes in other pharmacokinetic parameters [68]. In our own studies, terbinafine has increased CYP3A4 mRNA expression in primary human hepatocytes between 5-10 µM (unpublished).…”

Determination of terbinafine in tissues

“…The extensive tissue distribution, characterized by a large volume of distribution, significantly influences the half-life of terbinafine. The apparent volume of distribution is relatively large and in the range of 780-2000 L Jensen, 1989;Kovarik et al, 1992Kovarik et al, , 1995Nejjam et al, 1995;Robbins et al, 1996). The apparent volume of distribution is relatively large and in the range of 780-2000 L Jensen, 1989;Kovarik et al, 1992Kovarik et al, , 1995Nejjam et al, 1995;Robbins et al, 1996).…”

“…Terbinafine is highly lipophilic and keratophilic and as a result extensively distributes to adipose tissues, dermis, epidermis and nails (Faergemann et al, 1993). The terminal half-life for terbinafine in humans was reported in different studies to range from 15 h (Nejjam et al, 1995), to 26 h (Kovarik et al, 1992), 290 h (Robbins et al, 1996) and up to 22 days (Zehender et al, 1994). The terminal half-life for terbinafine in humans was reported in different studies to range from 15 h (Nejjam et al, 1995), to 26 h (Kovarik et al, 1992), 290 h (Robbins et al, 1996) and up to 22 days (Zehender et al, 1994).…”