title: Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men.
abstract: Potent CYP3A4 inhibitors such as ketoconazole can cause dangerous increases in plasma concentrations of the H-1 antagonist terfenadine. In light of recent reports that the selective serotonin reuptake inhibitor antidepressants may be weak CYP3A4 inhibitors, this study was designed 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 crossover study. Terfenadine (60 mg twice daily for 8 days) was administered alone and with paroxetine at steady state (20 mg once daily for 15 days, with terfenadine on days 8 through 15). Extensive electrocardiogram monitoring was conducted throughout, and terfenadine and carboxyterfenadine pharmacokinetics were assessed at the end of each treatment period. One subject withdrew because of adverse experiences related to paroxetine, but the other 11 subjects completed the study uneventfully. On the final day of coadministration, the rate-corrected QT interval (QTc) was unaltered compared with terfenadine dosed alone; maximum QTc values (mean [SEM]) were 404 (4) and 405 (5) msec, respectively. Terfenadine pharmacokinetics were also unchanged; geometric mean steady-state area under the curve (AUC)tau values were 30.0 ng.hr/mL during coadministration compared with 30.8 ng.hr/mL when dosed alone (p > 0.05). The corresponding Cmax values were 3.68 and 3.64 ng/mL (p > 0.05). There was, however, a small (on average 17-20%), unexplained reduction in the steadystate Cmax and AUCtau of carboxyterfenadine during coadministration with paroxetine. In conclusion, paroxetine does not affect the pharmacokinetics or cardiovascular effects of terfenadine. The small reduction in carboxyterfenadine plasma concentrations is unlikely to be important clinically.
authors.affiliation: SmithKline Beecham Clinical Pharmacology Unit, Presbyterian Medical Center of Philadelphia, University of Pennsylvania Health System, USA. martind@pharmaresearch.com
authors.forename: D E
authors.initials: DE
authors.lastname: Martin
authors.forename: B D
authors.initials: BD
authors.lastname: Zussman
authors.forename: D E
authors.initials: DE
authors.lastname: Everitt
authors.forename: L J
authors.initials: LJ
authors.lastname: Benincosa
authors.forename: R C
authors.initials: RC
authors.lastname: Etheredge
authors.forename: D K
authors.initials: DK
authors.lastname: Jorkasky
mesh_terms: D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006261:Headache / Q000139:chemically induced; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D017374:Paroxetine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D016593:Terfenadine / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D006634:Histamine H1 Antagonists; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D016593:Terfenadine