title: Effect of esomeprazole with/without acetylsalicylic acid, omeprazole and lansoprazole on pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers.
abstract: OBJECTIVE
  The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies.
  
  
  METHODS
  Study 1: subjects received clopidogrel alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation.
  
  
  RESULTS
  There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination.
  
  
  CONCLUSIONS
  Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination.
authors.affiliation: AstraZeneca R&D, Pepparedsleden 1, 431 83, Mölndal, Sweden, tommy.andersson@astrazeneca.com.
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.forename: Mohammad
authors.initials: M
authors.lastname: Niazi
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
authors.forename: Hal
authors.initials: H
authors.lastname: Galbraith
authors.forename: Santosh
authors.initials: S
authors.lastname: Ranjan
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D064098:Esomeprazole / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D064747:Lansoprazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D000077144:Clopidogrel; D009853:Omeprazole; D064098:Esomeprazole; D013988:Ticlopidine; D001241:Aspirin