No Effect of Omega-3 Carboxylic Acids on Pharmacokinetics/Pharmacodynamics of Warfarin or on Platelet Function When Co-administered with Acetylsalicylic Acid: Results of Two Phase I Studies in Healthy Volunteers

Abstract

Background

Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels.

Objective

Our objective was to assess the effects of OM3-CA on warfarin pharmacokinetics and pharmacodynamics and on acetylsalicylic acid (ASA)-dependent and independent platelet activation when co-administered with ASA in two phase I studies.

Methods

In ECLIPSE II (NCT01431690), 26 participants received warfarin 25 mg on days 1 and 22 and OM3-CA 4 g once daily from day 8 to day 28. In OM-EPA-007 (NCT01486433), 52 participants received simvastatin 40 mg plus ASA 81 mg once daily for 14 days, with or without OM3-CA 4 g. Lack of a drug–drug interaction was indicated when 90% confidence intervals (CIs) fell entirely within the range 80–125% for least-squares mean (LSM) ratios of area under the concentration–time curve (AUC), maximum observed plasma concentration (C max), international normalized ratio (INR) AUC to 168 h and maximum INR.

Results

In ECLIPSE II, 90% CIs for LSM ratios of with:without OM3-CA fell within 80–125% for AUC and C max of S- and R-warfarin enantiomers. The 90% CIs for LSM ratios of with:without OM3-CA fell within 80–125% for INR AUC to 168 h after dosing and for maximum INR of warfarin. In OM-EPA-007, no significant effect of OM3-CA was observed on ASA-dependent or ASA-independent platelet activation. No deaths or serious adverse events occurred in either study.

Conclusion

OM3-CA did not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacodynamic effects of ASA. OM3-CA did not affect platelet function when co-administered with ASA.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626–35. doi:10.1016/S0140-6736(14)61177-6.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol. 2014;13:159. doi:10.1186/s12933-014-0159-y.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014;8(1):94–106. doi:10.1016/j.jacl.2013.10.003.

    Article  PubMed  Google Scholar 

  4. 4.

    Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol. 2012;6(6):573–84. doi:10.1016/j.jacl.2012.01.002.

    Article  PubMed  Google Scholar 

  5. 5.

    Offman E, Marenco T, Ferber S, Johnson J, Kling D, Curcio D, et al. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study. Vasc Health Risk Manag. 2013;9:563–73. doi:10.2147/VHRM.S50464.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Department of Health and Human Services US Food, and Drug Administration. Substances affirmed as generally recognized as safe: menhaden oil. Fed Regist. 1997;62(108):30751–7.

    Google Scholar 

  7. 7.

    Harris WS, Windsor SL. N-3 fatty acid supplements reduce chylomicron levels in healthy volunteers. J Appl Nutr. 1991;43(1):5–15.

    CAS  Google Scholar 

  8. 8.

    Jain AP, Aggarwal KK, Zhang PY. Omega-3 fatty acids and cardiovascular disease. Eur Rev Med Pharmacol Sci. 2015;19(3):441–5.

    CAS  PubMed  Google Scholar 

  9. 9.

    Mortensen JZ, Schmidt EB, Nielsen AH, Dyerberg J. The effect of N-6 and N-3 polyunsaturated fatty acids on hemostasis, blood lipids and blood pressure. Thromb Haemost. 1983;50(2):543–6.

    CAS  PubMed  Google Scholar 

  10. 10.

    Vanschoonbeek K, de Maat MP, Heemskerk JW. Fish oil consumption and reduction of arterial disease. J Nutr. 2003;133(3):657–60.

    CAS  PubMed  Google Scholar 

  11. 11.

    Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, et al. Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects. Thromb Haemost. 2008;100(4):634–41.

    CAS  PubMed  Google Scholar 

  12. 12.

    Eritsland J, Arnesen H, Seljeflot I, Kierulf P. Long-term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul Fibrinolysis. 1995;6(1):17–22.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother. 2004;38(1):50–2.

    Article  PubMed  Google Scholar 

  14. 14.

    Jalili M, Dehpour AR. Extremely prolonged INR associated with warfarin in combination with both trazodone and omega-3 fatty acids. Arch Med Res. 2007;38(8):901–4. doi:10.1016/j.arcmed.2007.05.004.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther. 1974;15(4):424–30.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73(1):67–74.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol. 1992;5(1):54–9.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Harder S, Thurmann P. Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet. 1996;30(6):416–44.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    BioCytex. PLT VASP/P2Y12 for the monitoring of specific platelet ADP receptor antagonists (test kit brochure). Marseilles, France.

  20. 20.

    Corgenix Inc. AspirinWorks® test kit brochure.

  21. 21.

    Gao LG, Cao J, Mao QX, Lu XC, Zhou XL, Fan L. Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2013;226(2):328–34. doi:10.1016/j.atherosclerosis.2012.10.056.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    McEwen BJ, Morel-Kopp MC, Chen W, Tofler GH, Ward CM. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost. 2013;39(1):25–32. doi:10.1055/s-0032-1333309.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Serebruany VL, Miller M, Pokov AN, Lynch D, Jensen JK, Hallen J, et al. Early impact of prescription omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia. Cardiology. 2011;118(3):187–94. doi:10.1159/000329300.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Braeckman RA, Stirtan WG, Soni PN. Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetic and anticoagulation parameters. Clin Drug Investig. 2014;34(7):449–56. doi:10.1007/s40261-014-0194-1.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Pryce R, Bernaitis N, Davey AK, Badrick T, Anoopkumar-Dukie S. The use of fish oil with warfarin does not significantly affect either the international normalised ratio or incidence of adverse events in patients with atrial fibrillation and deep vein thrombosis: a retrospective study. Nutrients. 2016;8(9):578.

    Article  PubMed Central  Google Scholar 

  26. 26.

    Guirguis-Blake JM, Evans CV, Senger CA, Rowland MG, O’Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force Rockville (MD): Agency for Healthcare Research and Quality (US); 2015. Report No: 13-05195-EF-1.

  27. 27.

    Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–60. doi:10.1016/S0140-6736(09)60503-1.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Medical writing support was provided by Dr. Anja Becher of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca. The authors thank Doug Kling and Judith Johnson for their participation in aspects of the study design, Sandra Connolly for her involvement in the study conduct, and David Katzer for the statistical analyses.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Elliot Offman.

Ethics declarations

Funding

These studies were sponsored by AstraZeneca.

Conflict of interest

Elliot Offman was an employee of Celerion at the time that the manuscript was developed; Celerion received research funding for participation in these studies from Omthera Pharmaceuticals, which is a subsidiary of AstraZeneca. Michael Davidson was an employee of AstraZeneca at the time that the manuscript was developed. Catarina Nilsson is an employee of AstraZeneca.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Offman, E., Davidson, M. & Nilsson, C. No Effect of Omega-3 Carboxylic Acids on Pharmacokinetics/Pharmacodynamics of Warfarin or on Platelet Function When Co-administered with Acetylsalicylic Acid: Results of Two Phase I Studies in Healthy Volunteers. Am J Cardiovasc Drugs 17, 251–260 (2017). https://doi.org/10.1007/s40256-017-0217-4

Download citation

Keywords

  • Warfarin
  • International Normalize Ratio
  • Warfarin Dose
  • Aspirin Resistance
  • P2Y12 Reaction Unit