Safe coadministration of terbinafine and terfenadine: a placebo-controlled crossover study of pharmacokinetic and pharmacodynamic interactions in healthy volunteers.
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.
Robbins
B
B
Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Chang
C T
CT
Cramer
J A
JA
Garreffa
S
S
Hafkin
B
B
Hunt
T L
TL
Meligeni
J
J
D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values; D000077291:Terbinafine; D016593:Terfenadine / Q000008:administration & dosage / Q000494:pharmacology*
D000935:Antifungal Agents; D006634:Histamine H1 Antagonists; D009281:Naphthalenes; D016593:Terfenadine; D000077291:Terbinafine