A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State.
A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State.
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DOI：
10.1097/mjt.0000000000000247
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发表时间：
2015-09
影响因子：
4.2
通讯作者：
Ghahramani P
中科院分区：
文献类型：
--
作者：
Chen CL;Desai-Krieger D;Ortiz S;Kerolous M;Wright HM;Ghahramani P
联合不同类别的抗高血压药物比增加单一疗法的剂量更能有效降低血压 (BP)。这项 I 期研究的目的是研究血管舒张 β1 选择性阻滞剂奈必洛尔和血管紧张素 II 受体阻滞剂缬沙坦之间的药代动力学和药效学相互作用，并评估组合的安全性和耐受性。这是一项单中心、随机、开放标签、多剂量、三向交叉试验，受试者为 30 名 18-45 岁的健康成年人。参与者被随机分为 6 种治疗序列中的一种 (1:1:1:1:1:1)，包括三个为期 7 天的治疗期和随后的 7 天清除期。每日一次口服治疗包括奈必洛尔（20 mg）、缬沙坦（320 mg）和奈必洛尔-缬沙坦组合（20/320 mg）。结果包括 AUC0-τ,ss、Cmax,ss、Tmax,ss、血压变化、脉率、血浆血管紧张素 II、血浆肾素活性、24 小时尿醛固酮和不良事件。观察到稳态药代动力学相互作用，但认为没有临床意义。奈必洛尔-缬沙坦联合治疗的收缩压和舒张压降低效果显着高于任一单一疗法。与奈必洛尔和奈必洛尔-缬沙坦治疗相关的平均脉率始终低于与缬沙坦单药治疗相关的平均脉率。接受缬沙坦治疗的受试者中平均第 7 天血浆肾素活性和血浆血管紧张素 II 的急剧增加在同时服用奈必洛尔后显着减弱。与任一单一疗法相比，联合治疗后第 7 天的平均 24 小时尿醛固酮显着降低。所有治疗均安全且耐受性良好。总之，与单一疗法相比，奈必洛尔和缬沙坦联合用药可显着降低血压。奈必洛尔和缬沙坦通过互补机制降低血压。
Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18–45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol–valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol–valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol–valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.