PAROXETINE DOES NOT AFFECT THE CARDIAC SAFETY AND PHARMACOKINETICS OFTERFENADINE IN HEALTHY ADULT MEN

Potent CYP3A4 inhibitors such as ketoconazole can cause dangerous incr eases in plasma concentrations of the H-1 antagonist terfenadine. In l ight of recent reports that the selective serotonin reuptake inhibitor antidepressants may be weak CYP3A4 inhibitors, this study was designe d to investigate the effects of paroxetine on the pharmacodynamic and pharmacokinetic profile of terfenadine. Twelve healthy male volunteers participated in a randomized open-label, two-period, steady-state cro ssover study. Terfenadine (60 mg twice daily for 8 days) was administe red alone and with paroxetine at steady state (20 mg once daily for 15 days, with terfenadine on days 8 through 15). Extensive electrocardio gram monitoring was conducted throughout, and terfenadine and carboxyt erfenadine pharmacokinetics were assessed at the end of each treatment period. One subject withdrew because of adverse experiences related t o paroxetine, but the other 11 subjects completed the study uneventful ly. On the final day of coadministration, the rate-corrected QT interv al (QT(c)) was unaltered compared with terfenadine dosed alone; maximu m QT(c) values (mean [SEM]) were 404 (4) and 405 (5) msec, respectivel y. Terfenadine pharmacokinetics were also unchanged; geometric mean st eady-state area under the curve (AUC)(tau) values were 30.0 ng.hr/ml d uring coadministration compared with 30.8 ng.hr/mL when dosed alone (p > 0.05). The corresponding C-max values were 3.68 and 3.64 ng/mL Cp > 0.05). There was, however, a small (on average 17-20%), unexplained r eduction in the steady-state C-max and AUC(tau) of carboxyterfenadine during coadministration with paroxetine. In conclusion, paroxetine doe s not affect the pharmacokinetics or cardiovascular effects of terfena dine. The small reduction in carboxyterfenadine plasma concentrations is unlikely to be important clinically.