Systemic Bioavailability and Dose Proportionality of Omega-3 Administered in Free Fatty Acid Form Compared With Ethyl Ester Form: Results of a Phase 1 Study in Healthy Volunteers

Abstract

Background

Omega-3 carboxylic acids (OM3-CA) contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in free fatty acid form. Per gram, OM3-CA includes approximately half as much EPA as icosapent ethyl (IPE), an ethyl ester formulation of EPA.

Objective

The study aim was to assess systemic EPA and EPA + DHA exposures and plasma lipid parameters following multiple OM3-CA or IPE doses under low-fat dietary conditions, and dose proportionality after OM3-CA administration.

Methods

In this phase 1, two-cohort, open-label study (N = 114), participants following the Therapeutic Lifestyle Changes diet received either OM3-CA 2 g once daily for 10 days then OM3-CA 4 g once daily for 10 days, or IPE 2 g twice daily for 20 days. Exposure was considered similar if the 90% confidence intervals (CIs) of geometric least-squares mean (LSM) ratios for key pharmacokinetic parameters were within 80–125%.

Results

Baseline-adjusted steady-state EPA exposure was similar after dosing with OM3-CA 4 g/day versus IPE 4 g/day (LSM ratio, area under the concentration–time curve from time 0 to 24 h: 93.9%; 90% CI 85.6, 103.0). Combined molar-equivalent EPA + DHA exposure was 30.6% higher following OM3-CA 4 g/day than IPE 4 g/day. EPA and DHA exposure increased approximately proportionally with OM3-CA dose (2–4 g/day). Changes from baseline in lipid parameters were similar in the two cohorts.

Conclusion

EPA exposure from OM3-CA and IPE was similar under low-fat dietary conditions, despite OM3-CA containing only approximately half as much EPA as IPE. EPA and DHA exposure from OM3-CA increased proportionally with dose.

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Acknowledgements

Medical writing support was provided by Dr Anja Becher of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca. We 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.

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Correspondence to Elliot Offman.

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Ethical approval

All procedures performed in this study were in accordance with the 1964 Helsinki declaration (and its amendments). The study protocol underwent review by the Chesapeake Research Review Inc. Institutional Review Board (Columbia, MD, USA) in compliance with US Code of Federal Regulations and International Conference on Harmonisation guidelines. All participants provided their written informed consent.

Funding

This study was sponsored by AstraZeneca.

Conflict of interest

Elliot Offman, Mohammad Abu-Rashid and Peng Chai are employees of Celerion, which received research funding for participation in this study from Omthera Pharmaceuticals, which is a subsidiary of AstraZeneca. Michael Davidson was an employee of AstraZeneca at the time that the study was conducted. Catarina Nilsson is an employee of AstraZeneca.

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Offman, E., Davidson, M., Abu-Rashid, M. et al. Systemic Bioavailability and Dose Proportionality of Omega-3 Administered in Free Fatty Acid Form Compared With Ethyl Ester Form: Results of a Phase 1 Study in Healthy Volunteers. Eur J Drug Metab Pharmacokinet 42, 815–825 (2017). https://doi.org/10.1007/s13318-016-0398-2

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Keywords

  • Ethyl Ester
  • Dose Proportionality
  • Therapeutic Lifestyle Change
  • Free Fatty Acid Form
  • Icosapent Ethyl