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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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.
Study Design and Setting
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.
Main Outcome Measures
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.
KeywordsPlatelet Aggregation Omeprazole Dipyridamole Proton Pump Inhibitor Omeprazole Aggrenox
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript. This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors confirm that the paper is an accurate representation of the study results. The study sponsor had a role in the study design, the collection, analysis, and interpretation of data, the writing of the manuscript, and the decision to submit the paper for publication.
Conflict of Interest
Elliot Offman is a paid employee of Celerion Inc., which was contracted by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) to conduct this study, and has also received support from BIPI for travel to a congress at which the study data were presented. Michael J. Schobelock is a paid employee of BIPI. Rolf Brickl is a former employee of BIPI and was a paid consultant to BIPI at the time of the study and during manuscript preparation. Cam P. VanderMaelen is a paid employee of BIPI. Jerome Ehrlich is a paid employee of BIPI. Wolfgang Eisert was a paid employee of BIPI when the study was conducted and is now Professor of Medicine and Physics and Director of the Center for Thrombosis and Atherosclerosis Research, Hannover, Germany, a non-profit organization.
Writing, editorial support, and formatting assistance was provided by Helen Varley, PhD, of UBC-Envision Group (Horsham, UK), which was contracted and compensated by BIPI for these services.
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