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

Kevin C. Maki, Colleen Johns, William S. Harris, Mark Puder, Steven D. Freedman, Thorsteinn Thorsteinsson, Ahmed Daak, Adrian L. Rabinowicz, Frederick D. Sancilio

Research output: Research - peer-reviewArticle

  • 1 Citations

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The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters),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 This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions.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.

LanguageEnglish (US)
JournalClinical Therapeutics
DOIs
StateAccepted/In press - 2017
Externally publishedYes

Fingerprint

Therapeutic Equivalency
Esters
Acids
Eicosapentaenoic Acid
Fasting
United States Food and Drug Administration
Lipids
4,7,10,13,16,19-docosahexaenoic acid ethyl ester
ethyl eicosapentaenoic acid
Docosahexaenoic Acids
eicosapentaenoic acid ethyl ester
Hypertriglyceridemia
Prodrugs
Triglycerides

Keywords

  • Bioequivalence
  • Docosahexaenoic acid
  • Eicosapentaenoic acid
  • Ethyl esters ω-3 fatty acids
  • Triglycerides

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations : Rationale for Modification of Current Guidance. / Maki, Kevin C.; Johns, Colleen; Harris, William S.; Puder, Mark; Freedman, Steven D.; Thorsteinsson, Thorsteinn; Daak, Ahmed; Rabinowicz, Adrian L.; Sancilio, Frederick D.

In: Clinical Therapeutics, 2017.

Research output: Research - peer-reviewArticle

Maki, Kevin C. ; Johns, Colleen ; Harris, William S. ; Puder, Mark ; Freedman, Steven D. ; Thorsteinsson, Thorsteinn ; Daak, Ahmed ; Rabinowicz, Adrian L. ; Sancilio, Frederick D./ Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations : Rationale for Modification of Current Guidance. In: Clinical Therapeutics. 2017
@article{d520f187b06e4ab3bb6ffc1dbe617389,
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.",
keywords = "Bioequivalence, Docosahexaenoic acid, Eicosapentaenoic acid, Ethyl esters ω-3 fatty acids, Triglycerides",
author = "Maki, {Kevin C.} and Colleen Johns and Harris, {William S.} and Mark Puder and Freedman, {Steven D.} and Thorsteinn Thorsteinsson and Ahmed Daak and Rabinowicz, {Adrian L.} and Sancilio, {Frederick D.}",
year = "2017",
doi = "10.1016/j.clinthera.2017.01.019",
journal = "Clinical Therapeutics",
issn = "0149-2918",
publisher = "Excerpta Medica",

}

TY - JOUR

T1 - Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations

T2 - Clinical Therapeutics

AU - Maki,Kevin C.

AU - Johns,Colleen

AU - Harris,William S.

AU - Puder,Mark

AU - Freedman,Steven D.

AU - Thorsteinsson,Thorsteinn

AU - Daak,Ahmed

AU - Rabinowicz,Adrian L.

AU - Sancilio,Frederick D.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Bioequivalence

KW - Docosahexaenoic acid

KW - Eicosapentaenoic acid

KW - Ethyl esters ω-3 fatty acids

KW - Triglycerides

UR - http://www.scopus.com/inward/record.url?scp=85011878194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011878194&partnerID=8YFLogxK

U2 - 10.1016/j.clinthera.2017.01.019

DO - 10.1016/j.clinthera.2017.01.019

M3 - Article

JO - Clinical Therapeutics

JF - Clinical Therapeutics

SN - 0149-2918

ER -