Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

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 simulta...

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Published in:Clinical pharmacology and therapeutics 2011-01, Vol.89 (1), p.65-74
Main Authors: Angiolillo, D J, Gibson, C M, Cheng, S, Ollier, C, Nicolas, O, Bergougnan, L, Perrin, L, LaCreta, F P, Hurbin, F, Dubar, M
Format: Article
Language:English
Subjects:
2-Pyridinylmethylsulfinylbenzimidazoles - administration & dosage
2-Pyridinylmethylsulfinylbenzimidazoles - adverse effects
2-Pyridinylmethylsulfinylbenzimidazoles - pharmacology
Adult
Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors
Cross-Over Studies
Cytochrome P-450 CYP2C19
Double-Blind Method
Drug Administration Schedule
Drug Interactions
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - adverse effects
Enzyme Inhibitors - pharmacology
Female
Half-Life
Humans
Male
Middle Aged
Omeprazole - administration & dosage
Omeprazole - adverse effects
Omeprazole - pharmacology
Platelet Activation - drug effects
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - blood
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Aggregation Inhibitors - pharmacology
Prodrugs - adverse effects
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Proton Pump Inhibitors - administration & dosage
Proton Pump Inhibitors - adverse effects
Proton Pump Inhibitors - pharmacology
Ticlopidine - analogs & derivatives
Ticlopidine - blood
Ticlopidine - pharmacokinetics
Ticlopidine - pharmacology
Young Adult
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Summary: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 AUC0–24 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
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2010.219