Pharmacokinetics and Pharmacodynamics of the Antiplatelet Combination Aspirin (Acetylsalicylic Acid) Plus Extended-Release Dipyridamole Are Not Altered by Coadministration with the Potent CYP2C19 Inhibitor Omeprazole

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Abstract

Background

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.

Objective

This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA + ER-DP.

Study Design and Setting

This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit.

Participants

Sixty healthy male and female volunteers aged 18–50 years were included in the study.

Intervention

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.

Main Outcome Measures

The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation.

Results

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.

Conclusion

The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.

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