Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance.

Abstract

The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters), used to treat severe hypertriglyceridemia, recommends the conduct of 2 studies: one with participants in the fasting state and one with participants in the fed state. For the fasting study, the primary measures of BE are baseline-adjusted EPA and DHA levels in total plasma lipids. For the fed study, the primary measures of BE are EPA and DHA ethyl esters in plasma. This guidance differs from that established for icosapent ethyl (EPA ethyl esters) in which the primary measure of BE is baseline-adjusted total EPA in plasma lipids for both the fasting and fed states. The FDA guidance for ω-3 acid ethyl esters is not supported by their physiologic characteristics and triglyceride-lowering mechanisms because EPA and DHA ethyl esters are best characterized as pro-drugs. This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions. This change would harmonize the approaches for demonstration of BE for ω-3 acid ethyl esters and icosapent ethyl (EPA ethyl esters) products for future development programs and is the most physiologically rational approach to BE testing.

• Authors: Kevin C Maki, Colleen Johns, William S Harris, Mark Puder, Steven D Freedman, Thorsteinn Thorsteinsson, Ahmed Daak, Adrian L Rabinowicz, Frederick D Sancilio
• Journal: Clinical therapeutics (Clin Ther) Vol. 39 Issue 3 Pg. 652-658 (Mar 2017) ISSN: 1879-114X [Electronic] United States
• PMID: 28189365 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Chemical References

• Fatty Acids, Omega-3
• Hypolipidemic Agents
• Prodrugs
• Triglycerides
• Docosahexaenoic Acids
• eicosapentaenoic acid ethyl ester
• 4,7,10,13,16,19-docosahexaenoic acid ethyl ester
• Eicosapentaenoic Acid

Topics

• Docosahexaenoic Acids (pharmacokinetics)
• Eicosapentaenoic Acid (analogs & derivatives, pharmacokinetics)
• Fatty Acids, Omega-3 (pharmacokinetics, therapeutic use)
• Humans
• Hypertriglyceridemia (drug therapy)
• Hypolipidemic Agents (therapeutic use)
• Prodrugs (therapeutic use)
• Therapeutic Equivalency
• Triglycerides (blood)