Clinical Pharmacology Sciences, Celerion, 100 Boulevard Alexis-Nihon, Bureau (Suite) 360, Montreal, QC, H4M 2N8, Canada.
Am J Cardiovasc Drugs. 2013 Apr;13(2):113-20. doi: 10.1007/s40256-013-0018-3.
The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA+ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA+ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted.
This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA+ER-DP.
This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit.
Sixty healthy male and female volunteers aged 18-50 years were included in the study.
Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of ≥14 days between the second and third treatments. Treatment A=ASA+ER-DP 25 mg/200 mg (Aggrenox®) twice daily (BID) alone; B=ASA+ER-DP 25 mg/200 mg BID+omeprazole (Prilosec®) 80 mg once daily (QD) following ASA+ER-DP alone for 7 days; C=omeprazole 80 mg QD alone; D=omeprazole 80 mg QD+ASA+ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days.
The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation.
Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC0-12,ss, ng·h/mL) and maximum plasma concentration (Cmax,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90% confidence interval [CI] 90.96-102.13) for AUC0-12,ss and 92.03 (86.95-97.40) for Cmax,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32-99.72) at 4 h after last dose. All treatments were well tolerated.
The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.
阿司匹林（乙酰水杨酸）25 毫克加缓释双嘧达莫 200 毫克的固定剂量组合（ASA+ER-DP）用于预防经历过非心源性卒中和短暂性脑缺血发作的患者的长期二级卒中。虽然同时使用质子泵抑制剂（PPI）可能会影响 ASA+ER-DP 的抗血小板活性的理论风险较低，但尚未进行正式的药物相互作用研究。
本研究旨在确定质子泵抑制剂奥美拉唑是否会影响 ASA+ER-DP 的药代动力学（PK）和药效学（PD）行为。
这是一项在临床试验单位进行的随机、开放标签、多剂量、交叉、药物相互作用研究。
60 名年龄在 18-50 岁之间的健康男性和女性志愿者被纳入研究。
参与者被随机分配到两种治疗序列之一（ABCD 或 CDAB），每个序列包括四个 7 天的治疗期，第二次和第三次治疗之间有 14 天以上的洗脱期。治疗 A=ASA+ER-DP 25 毫克/200 毫克（Aggrenox®）每日两次（BID）单独使用；B=ASA+ER-DP 25 毫克/200 毫克 BID+奥美拉唑（Prilosec®）80 毫克每日一次（QD）在 ASA+ER-DP 单独使用 7 天后使用；C=奥美拉唑 80 毫克 QD 单独使用；D=奥美拉唑 80 毫克 QD+ASA+ER-DP 25 毫克/200 毫克 BID 在奥美拉唑单独使用 7 天后使用。
主要观察指标是 ER-DP 的全身 PK 暴露和阿司匹林抑制花生四烯酸诱导的血小板聚集。
基于从 0 到 12 小时的稳态浓度-时间曲线下面积（AUC）（AUC0-12,ss，ng·h/mL）和最大血浆浓度（Cmax，ss，ng/mL），奥美拉唑对 ER-DP 的全身暴露与没有奥美拉唑时相似。对于治疗比较 D 与 A，AUC0-12,ss 的百分比均值比为 96.38（90%置信区间 [CI] 90.96-102.13），Cmax,ss 的百分比均值比为 92.03（86.95-97.40）。ER-DP 的浓度-时间曲线几乎重叠。对阿司匹林成分的 PD 没有影响：在最后一次给药后 4 小时，奥美拉唑对阿司匹林抑制花生四烯酸诱导的血小板聚集的抑制作用几乎相同，治疗 D 与 A 的百分比均值比为 99.02（90%置信区间 98.32-99.72）。所有治疗均耐受良好。
同时使用奥美拉唑不会改变 ASA+ER-DP 的 PK 和 PD 行为。
