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Effect of Esomeprazole With/Without Acetylsalicylic Acid, Omeprazole and Lansoprazole on Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Volunteers

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Abstract

Objective

The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies.

Subjects and 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.

Conclusion

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.

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Acknowledgments

This study was supported by AstraZeneca R&D, Mölndal, Sweden. Medical writing support was provided by Lisa M. Klumpp Callan and Steve Winter of inScience Communications, Springer Healthcare and funded by AstraZeneca.

Conflicts of interest/Disclosure

T. Andersson, P. Nagy, M. Niazi and S. Nylander are employees of AstraZeneca. H. Galbraith and S. Ranjan are employees of Quintiles, who conducted the studies with funding from AstraZeneca. L. Wallentin has received research grants from AstraZeneca.

Author Contributions

Study conception, design and monitoring, and interpretation of data: T. Andersson, P. Nagy, M. Niazi, and S. Nylander.

Study design, conduct, analysis and interpretation of data: H. Galbraith and S. Ranjan.

Interpretation of data: L. Wallentin.

All authors contributed to drafting of the article and approved the final version to be published.

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Authors and Affiliations

  1. AstraZeneca R&D, Pepparedsleden 1, 431 83, Mölndal, Sweden

    Tommy Andersson, Mohammad Niazi & Sven Nylander

  2. Global Medicines Department, AstraZeneca R&D, Mölndal, Sweden

    Peter Nagy

  3. Clinical Pharmacology, Quintiles, Kansas, USA

    Hal Galbraith

  4. Biostatistics, Quintiles, Kansas, USA

    Santosh Ranjan

  5. Uppsala Clinical Research Centre, Uppsala, Sweden

    Lars Wallentin

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  1. Tommy Andersson
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Correspondence to Tommy Andersson.

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Clinical Trial Registration Registered at ClinicalTrials.gov as NCT01147588 and NCT01210339.

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Andersson, T., Nagy, P., Niazi, M. et al. Effect of Esomeprazole With/Without Acetylsalicylic Acid, Omeprazole and Lansoprazole on Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Volunteers. Am J Cardiovasc Drugs 14, 217–227 (2014). https://doi.org/10.1007/s40256-014-0073-4

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