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Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo‐Controlled, Crossover Comparison Studies
Author(s) -
Angiolillo D J,
Gibson C M,
Cheng S,
Ollier C,
Nicolas O,
Bergougnan L,
Perrin L,
LaCreta F P,
Hurbin F,
Dubar M
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.219
Subject(s) - omeprazole , clopidogrel , pantoprazole , crossover study , pharmacology , drug interaction , proton pump inhibitor , pharmacodynamics , pharmacokinetics , medicine , placebo , chemistry , aspirin , pathology , alternative medicine
Four randomized, placebo‐controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300‐mg loading dose/75‐mg/day maintenance dose) and the proton‐pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600‐mg loading/150‐mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC 0–24 of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% ( P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 µmol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% ( P ≤ 0.014), respectively; and increased the vasodilator‐stimulated phosphoprotein phosphorylation‐platelet reactivity index (VASP‐PRI) by 20.7, 27.1, 19.0 ( P < 0.0001), and 3.9% ( P = 0.3319), respectively. The results suggest that a metabolic drug–drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole. Clinical Pharmacology & Therapeutics (2011) 89 1, 65–74. doi: 10.1038/clpt.2010.219