Document Detail


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.
MedLine Citation:
PMID:  22464259     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: 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:
Andrew L Frelinger; Ronald D Lee; Darcy J Mulford; Jingtao Wu; Sai Nudurupati; Anu Nigam; Julie K Brooks; Deepak L Bhatt; Alan D Michelson
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Publication Detail:
Type:  Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  59     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-02     Completed Date:  2012-05-17     Revised Date:  2013-01-07    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1304-11     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00942175
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MeSH Terms
Descriptor/Qualifier:
2-Pyridinylmethylsulfinylbenzimidazoles / administration & dosage*
Adult
Area Under Curve
Blood Coagulation / drug effects
Blood Platelets / drug effects
Confidence Intervals
Cross-Over Studies
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Interactions
Drug Therapy, Combination
Esomeprazole Sodium
Female
Humans
Male
Middle Aged
Omeprazole / administration & dosage*
Proton Pump Inhibitors / administration & dosage*
Reference Values
Ticlopidine / analogs & derivatives*,  pharmacokinetics
Young Adult
Chemical
Reg. No./Substance:
0/2-Pyridinylmethylsulfinylbenzimidazoles; 0/Proton Pump Inhibitors; 103577-45-3/lansoprazole; 55142-85-3/Ticlopidine; 73590-58-6/Omeprazole; A74586SNO7/clopidogrel; L2C9GWQ43H/Esomeprazole Sodium
Comments/Corrections
Erratum In:
J Am Coll Cardiol. 2012 Aug 7;60(6):566-7

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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