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
Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels.
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.
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.
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.
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.
KeywordsWarfarin International Normalize Ratio Warfarin Dose Aspirin Resistance P2Y12 Reaction Unit
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.
Compliance with Ethical Standards
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.
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