A Single-dose, Comparative Bioavailability Study of a Formulation containing OM3 as Phospholipid and Free Fatty Acid to an Ethyl Ester Formulation in the Fasting and Fed States

Abstract

Purpose: Formulations of ω (OM)-3 with adequate bioavailability in the low-fat fed state are advantageous in patients with severe hypertriglyceridemia (HTG), as these patients are advised to adhere to a low-fat diet. The OM3-containing prescription drugs approved by the US Food and Drug administration (FDA) provide OM3 in either ethyl ester (EE) or free fatty acid (FFA) forms. The OM3 FFA form and formulations with micelle-forming ability have shown improved bioavailability versus the EE form. OM3 phospholipid (PL)/FFA, a krill oil-derived OM3 mixture containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) present as PL esters and FFA, is being developed for the treatment of severe HTG. Both forms of OM3 in OM3-PL/FFA are believed to be digested and absorbed more efficiently as compared to OM3 in EE. This hypothesis was tested by comparing the relative bioavailabilities of EPA and DHA from a single 4-g dose administration of OM3-PL/FFA to those the FDA-approved HTG drug OM3-EE in the fed (high-fat meal) and fasted states. The effects of food on the bioavailability of both drugs were also tested.

Methods: This open-label, randomized, 4-way crossover bioavailability study was conducted in 56 healthy adults who were randomly assigned to receive a single 4-g dose of OM3-PL/FFA or OM3-EE in the fasted and fed (high-fat meal) states. The relative bioavailabilities of EPA and DHA were compared between the 2 formulations using pharmacokinetic analysis.

Findings: In the fasted state, the AUC_0-72 and C_max of EPA + DHA were 5- and 2.7-fold higher, respectively, with OM3-PL/FFA versus OM3-EE. These values were 3- and 4-fold lower in the fed state with OM3-PL/FFA versus OM3-EE. On administration of OM3-EE, the AUC_0-72 and C_{max of} EPA + DHA were 25- and 11-fold higher, respectively, in the fed versus the fasted state. A much lower increase (1.7-fold) in the AUC_0-72 of EPA + DHA was observed on administration of OM3-PL/FFA in the fed versus the fasted state, with similar C_max values.

Implications: These results demonstrate that the bioavailabilities of EPA and DHA with OM3-PL/FFA, as FFA and conjugated to PL, are far less affected by the fat content of a meal as compared to the EPA and DHA EEs in OM3-EE. These findings suggest a potential clinical advantage with OM3-PL/FFA, since patients with HTG are advised to follow a fat-restricted diet.

Keywords: bioavailability; docosahexaenoic acid; eicosapentaenoic acid; food effect; ω-3 phospholipids.