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.

摘要

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.