title: A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers.
abstract: OBJECTIVE
  The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel.
  
  
  BACKGROUND
  Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel.
  
  
  METHODS
  A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units.
  
  
  RESULTS
  Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units.
  
  
  CONCLUSIONS
  Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. andrew.frelinger@childrens.harvard.edu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Lee
authors.forename: Darcy J
authors.initials: DJ
authors.lastname: Mulford
authors.forename: Jingtao
authors.initials: J
authors.lastname: Wu
authors.forename: Sai
authors.initials: S
authors.lastname: Nudurupati
authors.forename: Anu
authors.initials: A
authors.lastname: Nigam
authors.forename: Julie K
authors.initials: JK
authors.lastname: Brooks
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage*; D000328:Adult; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D016001:Confidence Intervals; D018592:Cross-Over Studies; D064748:Dexlansoprazole; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D064098:Esomeprazole; D005260:Female; D006801:Humans; D064747:Lansoprazole; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D012016:Reference Values; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D000077144:Clopidogrel; D009853:Omeprazole; D064098:Esomeprazole; D013988:Ticlopidine; D064748:Dexlansoprazole