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. 2017 Oct;42(5):815-825. doi: 10.1007/s13318-016-0398-2.

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.

Keywords: Dose Proportionality; Ethyl Ester; Free Fatty Acid Form; Icosapent Ethyl; Therapeutic Lifestyle Change.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Biological Availability
  • Cohort Studies
  • Diet
  • Docosahexaenoic Acids / administration & dosage
  • Docosahexaenoic Acids / metabolism
  • Eicosapentaenoic Acid / administration & dosage
  • Eicosapentaenoic Acid / analogs & derivatives
  • Eicosapentaenoic Acid / metabolism
  • Esters / administration & dosage*
  • Esters / metabolism
  • Fatty Acids, Nonesterified / administration & dosage*
  • Fatty Acids, Nonesterified / metabolism*
  • Fatty Acids, Omega-3 / administration & dosage*
  • Fatty Acids, Omega-3 / metabolism*
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Young Adult

Substances

  • Esters
  • Fatty Acids, Nonesterified
  • Fatty Acids, Omega-3
  • Docosahexaenoic Acids
  • eicosapentaenoic acid ethyl ester
  • Eicosapentaenoic Acid