van der Lee Manon J, Blenke Audrey A M, Rongen Gerard A, Verwey-van Wissen Corrien P W G M, Koopmans Peter P, Pharo Cristina, Burger David M
Department of Clinical Pharmacy, Radboud University Medical Centre Nijmegen, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands.
Antimicrob Agents Chemother. 2007 Nov;51(11):4098-104. doi: 10.1128/AAC.01243-06. Epub 2007 Sep 10.
Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (C(max)), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t(1/2)). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC(0-12), C(max), C(min), and t(1/2) of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.
感染人类免疫缺陷病毒的患者患抑郁症的风险增加。尽管药物相互作用的可能性很大，但关于抗抑郁药和抗逆转录病毒药物联合使用的数据有限。从理论上讲，利托那韦增强的蛋白酶抑制剂可能会抑制CYP2D6介导的帕罗西汀代谢。我们想确定福沙那韦-利托那韦对帕罗西汀药代动力学的影响，反之亦然，并评估联合用药的安全性。A组开始时每天服用20毫克帕罗西汀，持续10天；在16天的洗脱期后，受试者在第28至37天接受帕罗西汀（每天20毫克）加福沙那韦-利托那韦（700/100毫克，每日两次）。B组按相反顺序接受治疗方案。在第10天和第37天记录药代动力学曲线。纳入了26名健康受试者（18名女性，8名男性）。年龄中位数（范围）和体重分别为44.4（18.2至64.3）岁和68.8（51.0至89.4）千克。三名受试者被排除（两名因不良事件；一名因不依从）。在帕罗西汀中添加福沙那韦-利托那韦导致帕罗西汀暴露量显著降低：帕罗西汀加福沙那韦-利托那韦与单独使用帕罗西汀相比，0至24小时浓度-时间曲线下面积（AUC(0-24)）的几何平均比值（90%置信区间）为0.45（0.41至0.49），血浆中药物的最大浓度（C(max)）为0.49（0.45至0.53），表观消除半衰期（t(1/2)）为0.75（0.71至0.80）。添加福沙那韦-利托那韦后，帕罗西汀的游离分数中位数（四分位间距）增加了30%（18%至42%）。安普那韦和利托那韦的AUC(0-12)、C(max)、C(min)和t(1/2)与历史对照相似。未发生严重不良事件。福沙那韦-利托那韦使帕罗西汀的总暴露量降低了55%。这部分可以用帕罗西汀的蛋白置换来解释。我们认为这种相互作用具有临床相关性，可能需要滴定至更高剂量的帕罗西汀才能达到所需的抗抑郁效果。
