Frost Charles, Song Yan, Yu Zhigang, Wang Jessie, Lee Lois S, Schuster Alan, Pollack Allyson, LaCreta Frank
Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Medical Sciences, Amgen Asia R&D Center, Shanghai, People's Republic of China.
Clin Pharmacol. 2017 Feb 23;9:19-28. doi: 10.2147/CPAA.S115687. eCollection 2017.
Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin (digoxin) and single-dose Tenormin (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies.
The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2-10, followed by apixaban 20 mg and digoxin 0.25 mg once daily on days 11-20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of apixaban 10 mg, atenolol 100 mg, or apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (C) and area under the concentration-time curve (AUC), with and without apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%-125% (digoxin) or 70%-143% (atenolol). A similar analysis was performed to assess the effect of atenolol on apixaban.
Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol C and AUC were entirely within their respective no-effect intervals. Apixaban C and AUC were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study.
Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between apixaban and atenolol. Coadministration of digoxin or atenolol with apixaban in healthy subjects was generally well tolerated.
阿哌沙班常与心血管合并症治疗药物联合使用，这可能导致意外的药物相互作用（DDIs）。在两项1期研究中，研究了阿哌沙班对多剂量地高辛（Lanoxin）和单剂量阿替洛尔（Tenormin）药代动力学（PK）的影响，以及单剂量阿替洛尔对健康受试者中阿哌沙班PK的影响。
地高辛药物相互作用研究是一项开放标签、多剂量、双治疗、单序列研究，受试者在第1天每6小时接受0.25mg地高辛，然后在第2 - 10天每天一次，随后在第11 - 20天每天一次接受20mg阿哌沙班和0.25mg地高辛。阿替洛尔药物相互作用研究是一项开放标签、单剂量、随机、三周期、三治疗、交叉研究，受试者接受单剂量口服10mg阿哌沙班、100mg阿替洛尔或10mg阿哌沙班加100mg阿替洛尔。计算了有和没有阿哌沙班时，峰血浆浓度（C）和浓度 - 时间曲线下面积（AUC）几何均值比值的90%置信区间（CIs）。如果点估计值和90%CI在80% - 125%（地高辛）或70% - 143%（阿替洛尔）的等效区间内，则得出无效应的结论。进行了类似分析以评估阿替洛尔对阿哌沙班的影响。
阿哌沙班对阿替洛尔或地高辛的PK均无临床相关影响：地高辛和阿替洛尔C及AUC的点估计值和90%CI完全在各自的无效应区间内。阿替洛尔联合给药后，阿哌沙班C和AUC略有下降（分别降低18%和15%）。两项研究期间均未报告严重或主要的出血相关不良事件。
阿哌沙班对地高辛的PK无影响，且阿哌沙班与阿替洛尔之间无临床相关相互作用。健康受试者中地高辛或阿替洛尔与阿哌沙班联合给药一般耐受性良好。
