title: 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.
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.
  
  
  METHODS
  This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit.
  
  
  METHODS
  Sixty healthy male and female volunteers aged 18-50 years were included in the study.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.
authors.affiliation: Clinical Pharmacology Sciences, Celerion, 100 Boulevard Alexis-Nihon, Bureau (Suite) 360, Montreal, QC, H4M 2N8, Canada. elliot.offman@celerion.com
authors.forename: Elliot
authors.initials: E
authors.lastname: Offman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schobelock
authors.forename: Rolf
authors.initials: R
authors.lastname: Brickl
authors.forename: Cam P
authors.initials: CP
authors.lastname: VanderMaelen
authors.forename: Jerome
authors.initials: J
authors.lastname: Ehrlich
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisert
mesh_terms: D000293:Adolescent; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068342:Aspirin, Dipyridamole Drug Combination; D018592:Cross-Over Studies; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000068342:Aspirin, Dipyridamole Drug Combination; D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D004176:Dipyridamole; D009853:Omeprazole; D001241:Aspirin