title: 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abstract: The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters),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 This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions.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.affiliation: Midwest Biomedical Research/Center for Metabolic and Cardiovascular Research and Department of Food Science and Nutrition, Illinois Institute of Technology, Chicago, Illinois. Electronic address: kmaki@mbclinicalresearch.com.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Maki
authors.affiliation: Sancilio and Company, Inc, Riviera Beach, Florida.
authors.forename: Colleen
authors.initials: C
authors.lastname: Johns
authors.affiliation: Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota; OmegaQuant Analytics, LLC, Sioux Falls, South Dakota.
authors.forename: William S
authors.initials: WS
authors.lastname: Harris
authors.affiliation: Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Puder
authors.affiliation: Division of Translational Research and Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Freedman
authors.affiliation: Sancilio and Company, Inc, Riviera Beach, Florida.
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Thorsteinsson
authors.affiliation: Sancilio and Company, Inc, Riviera Beach, Florida.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Daak
authors.affiliation: Sancilio and Company, Inc, Riviera Beach, Florida.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Rabinowicz
authors.affiliation: Sancilio and Company, Inc, Riviera Beach, Florida.
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Sancilio
mesh_terms: D004281:Docosahexaenoic Acids / Q000493:pharmacokinetics*; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015525:Fatty Acids, Omega-3 / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use; D013810:Therapeutic Equivalency; D014280:Triglycerides / Q000097:blood
chemical_list: D015525:Fatty Acids, Omega-3; D000960:Hypolipidemic Agents; D011355:Prodrugs; D014280:Triglycerides; D004281:Docosahexaenoic Acids; C035276:eicosapentaenoic acid ethyl ester; C067518:4,7,10,13,16,19-docosahexaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid
keywords: bioequivalence; docosahexaenoic acid; eicosapentaenoic acid; ethyl esters ω-3 fatty acids; triglycerides