Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men
Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men
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DOI：
10.1097/00004714-199712000-00003
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发表时间：
1997-12-01
影响因子：
2.9
通讯作者：
Jorkasky, DK
中科院分区：
文献类型：
--
作者：
Martin, DE;Zussman, BD;Jorkasky, DK
强有力的CYP3A4抑制剂，如酮康唑，可能会导致H-1拮抗剂特非那定的血浆浓度危险增加。鉴于最近报道的选择性5-羟色胺再摄取抑制剂抗抑郁药可能是弱的CYP3A4抑制剂，本研究旨在探讨帕罗西汀对特非那定药效学和药动学的影响。12名健康男性志愿者参与了一项随机开放标签、两期、稳态交叉研究。特非那丁(60 mg，每日两次，共8天)单独服用，帕罗西汀维持稳定状态(每天20 mg，共15天，特非那定8-15天)。在每个疗程结束时都进行了广泛的心电图监测，并评估了特非那定和羧特非那定的药代动力学。一名受试者因与帕罗西汀相关的不良反应而退出，但其他11名受试者顺利完成了研究。在联合给药的最后一天，心率校正的QT间期(QT(C))与单独给药相比没有变化，最大QT(C)值(平均值[SEM])分别为404(4)和405(5)毫秒。特非那定的药代动力学也没有变化；联合给药期间，几何平均稳态曲线下面积(AUC)(Tau)值为30.0ng.hr/ml，而单独给药时为30.8ng.hr/ml(p>；0.05)。相应的C-max分别为3.68和3.64 ng/mLCP>；0.05)。然而，在与帕罗西汀联合给药期间，羧特非那定的稳态C-max和AUC(Tau)有一个小的(平均17-20%)原因不明的下降。结论：帕罗西汀不影响特非那定的药代动力学或心血管效应。羧特非那定血药浓度的小幅降低在临床上不太可能是重要的。
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 (QT(c)) was unaltered compared with terfenadine dosed alone; maximum QT(c) 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 C-max values were 3.68 and 3.64 ng/mL Cp > 0.05). There was, however, a small (on average 17-20%), unexplained reduction in the steady-state C-max and AUC(tau) 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.