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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.