Advertisement

American Journal of Cardiovascular Drugs

, Volume 13, Issue 2, pp 113–120 | Cite as

Pharmacokinetics and Pharmacodynamics of the Antiplatelet Combination Aspirin (Acetylsalicylic Acid) Plus Extended-Release Dipyridamole Are Not Altered by Coadministration with the Potent CYP2C19 Inhibitor Omeprazole

  • Elliot OffmanEmail author
  • Michael J. Schobelock
  • Rolf Brickl
  • Cam P. VanderMaelen
  • Jerome Ehrlich
  • Wolfgang Eisert
Original Research Article

Abstract

Background

The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA + ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA + ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted.

Objective

This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA + ER-DP.

Study Design and Setting

This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit.

Participants

Sixty healthy male and female volunteers aged 18–50 years were included in the study.

Intervention

Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of ≥14 days between the second and third treatments. Treatment A = ASA + ER-DP 25 mg/200 mg (Aggrenox®) twice daily (BID) alone; B = ASA + ER-DP 25 mg/200 mg BID + omeprazole (Prilosec®) 80 mg once daily (QD) following ASA + ER-DP alone for 7 days; C = omeprazole 80 mg QD alone; D = omeprazole 80 mg QD + ASA + ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days.

Main Outcome Measures

The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation.

Results

Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC0–12,ss, ng·h/mL) and maximum plasma concentration (Cmax,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90 % confidence interval [CI] 90.96–102.13) for AUC0–12,ss and 92.03 (86.95–97.40) for Cmax,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32–99.72) at 4 h after last dose. All treatments were well tolerated.

Conclusion

The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.

Keywords

Platelet Aggregation Omeprazole Dipyridamole Proton Pump Inhibitor Omeprazole Aggrenox 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Funding

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript. This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors confirm that the paper is an accurate representation of the study results. The study sponsor had a role in the study design, the collection, analysis, and interpretation of data, the writing of the manuscript, and the decision to submit the paper for publication.

Conflict of Interest

Elliot Offman is a paid employee of Celerion Inc., which was contracted by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) to conduct this study, and has also received support from BIPI for travel to a congress at which the study data were presented. Michael J. Schobelock is a paid employee of BIPI. Rolf Brickl is a former employee of BIPI and was a paid consultant to BIPI at the time of the study and during manuscript preparation. Cam P. VanderMaelen is a paid employee of BIPI. Jerome Ehrlich is a paid employee of BIPI. Wolfgang Eisert was a paid employee of BIPI when the study was conducted and is now Professor of Medicine and Physics and Director of the Center for Thrombosis and Atherosclerosis Research, Hannover, Germany, a non-profit organization.

Additional Contributions

Writing, editorial support, and formatting assistance was provided by Helen Varley, PhD, of UBC-Envision Group (Horsham, UK), which was contracted and compensated by BIPI for these services.

References

  1. 1.
    Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):7S–47S.PubMedCrossRefGoogle Scholar
  2. 2.
    Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(1):227–76.PubMedCrossRefGoogle Scholar
  3. 3.
    Ringleb PA, Ford G, Bath P, et al. European Stroke Organization (ESO) Guidelines for management of ischaemic stroke and transient ischaemic attack 2008 (online). http://www.eso-stroke.org/recommendations.php. Accessed 29 May 2012.
  4. 4.
    Ancrenaz V, Daali Y, Fontana P, et al. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability. Curr Drug Metab. 2010;11(8):667–77.PubMedCrossRefGoogle Scholar
  5. 5.
    Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51(3):256–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008;52(18):1502–17.PubMedCrossRefGoogle Scholar
  8. 8.
    Boehringer Ingelheim International GmbH. Persantine® (dipyridamole USP) prescribing information 2006 (online). http://www.drugs.com/pro/persantine.html. Accessed 29 May 2012.
  9. 9.
    Boehringer Ingelheim International GmbH. AGGRENOX® (aspirin/extended-release dipyridamole) capsules prescribing information 2011 (online). http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Aggrenox+Caps/Aggrenox.pdf. Accessed 29 May 2012.
  10. 10.
    Russell TL, Berardi RR, Barnett JL, et al. pH-related changes in the absorption of dipyridamole in the elderly. Pharm Res. 1994;11(1):136–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Derendorf H, VanderMaelen CP, Brickl RS, et al. Dipyridamole bioavailability in subjects with reduced gastric acidity. J Clin Pharmacol. 2005;45(7):845–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Dunn SP, Macaulay TE. Drug-drug interactions associated with antiplatelet therapy. Cardiovasc Hematol Agents Med Chem. 2011;9(4):231–40.CrossRefGoogle Scholar
  13. 13.
    AstraZeneca Pharmaceuticals LP. PRILOSEC® (omeprazole) delayed-release capsules 2012 (online). http://www1.astrazeneca-us.com/pi/Prilosec.pdf. Accessed 29 May 2012.
  14. 14.
    Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008;48(4):475–84.PubMedCrossRefGoogle Scholar
  15. 15.
    U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research. Guidance for industry: Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations, Rockville, 2006.Google Scholar
  16. 16.
    U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: Bioavailability and bioequivalence studies for orally administered drug products—general considerations. Revision 1, 2003 (online). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf. Accessed 29 May 2012.
  17. 17.
    Cox D, Maree AO, Dooley M, et al. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke. 2006;37(8):2153–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation. 2007;115(25):3156–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Bode-Böger SM, Böger RH, Schubert M, et al. Effects of very low dose and enteric-coated acetylsalicylic acid on prostacyclin and thromboxane formation and on bleeding time in healthy subjects. Eur J Clin Pharmacol. 1998;54(9–10):707–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Lahner E, Annibale B, Delle Fave G. Systematic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment Pharmacol Ther. 2009;29(12):1219–29.PubMedCrossRefGoogle Scholar
  21. 21.
    Born G, Patrono C. Antiplatelet drugs. Br J Pharmacol. 2006;147(Suppl 1):S241–51.PubMedGoogle Scholar
  22. 22.
    Eisert WG. Dipyridamole. In: Michelson AD (ed) Platelets, 2nd edn. New York: Academic Press; 2007, p. 1165–79.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Elliot Offman
    • 1
    Email author
  • Michael J. Schobelock
    • 2
  • Rolf Brickl
    • 3
  • Cam P. VanderMaelen
    • 2
  • Jerome Ehrlich
    • 2
  • Wolfgang Eisert
    • 4
  1. 1.Clinical Pharmacology Sciences, CelerionMontrealCanada
  2. 2.Boehringer Ingelheim Pharmaceuticals, Inc.RidgefieldUSA
  3. 3.Boehringer Ingelheim GmbH & Co. KGIngelheimGermany
  4. 4.Department of NeurologyMedizinische Hochschule Hannover (MHH), and Center for Thrombosis and Atherosclerosis ResearchHannoverGermany

Personalised recommendations