title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Celerion, 100 Boulevard Alexis-Nihon, Bureau (Suite) 360, Montreal, QC, H4M 2N8, Canada. Elliot.offman@celerion.com.
authors.forename: Elliot
authors.initials: E
authors.lastname: Offman
authors.affiliation: Department of Cardiology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA.|Corvidia Therapeutics, Waltham, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Celerion, 100 Boulevard Alexis-Nihon, Bureau (Suite) 360, Montreal, QC, H4M 2N8, Canada.|Data Management and Biometrics, Celerion, Montreal, QC, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Rashid
authors.affiliation: Data Management and Biometrics, Celerion, Montreal, QC, Canada.
authors.forename: Peng
authors.initials: P
authors.lastname: Chai
authors.affiliation: Quantitive Clinical Pharmacology, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Nilsson
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D015331:Cohort Studies; D004032:Diet; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D004952:Esters / Q000008:administration & dosage* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage* / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D004952:Esters; D005230:Fatty Acids, Nonesterified; D015525:Fatty Acids, Omega-3; D004281:Docosahexaenoic Acids; C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid
keywords: Dose Proportionality; Ethyl Ester; Free Fatty Acid Form; Icosapent Ethyl; Therapeutic Lifestyle Change