Evaluation of OM3-PL/FFA Pharmacokinetics After Single and Multiple Oral Doses in Healthy Volunteers

Abstract

Purpose: The US Food and Drug Administration has approved several omega-3 (OM3)-containing prescription drugs for the treatment of severe hypertriglyceridemia (HTG). However, there is still a need to develop formulations with high bioavailability irrespective of the fat content and time of the meal. OM3-phospholipid (PL)/free fatty acid (FFA) is an investigational drug for the treatment of severe HTG containing naturally derived krill oil mixture of OM3, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as PL esters and as FFA. Both forms in OM3-PL/FFA are believed to be readily bioavailable. Per gram, OM3-PL/FFA contains a lower dose of EPA/DHA in comparison with already approved prescription drugs. The study aim was to evaluate OM3-PL/FFA pharmacokinetic (PK) properties after single and multiple oral doses of 1, 2, and 4 g in healthy subjects when receiving a Therapeutic Lifestyle Change (TLC) diet. The dose proportionality of the study drug, the effect of a high-fat (HF) meal on its PK properties and its safety profile after multiple administration were also explored.

Methods: In this Phase I, open-label, randomized, multiple-dose, single-center, parallel-design study, 42 healthy volunteers following a TLC diet were randomly assigned into 1 of 3 treatment groups in a 1:1:1 ratio to receive a single dose at day 1, followed by multiple oral doses of 1, 2, and 4 g/d for 14 days. At day 15, all subjects received a HF breakfast.

Findings: After once-daily dosing, based on graphic assessment, OM3-PL/FFA levels reached steady state within 7-10 days. Exposure of total EPA + DHA, total DHA, and total EPA (C_max and AUC) appeared to be approximately proportional over the 1-4 g/d dose range. After 14 days of repeated daily dosing, accumulation was observed and was greater at the higher dose of the study product. When administered after a HF breakfast on day 15, median t_max, the geometric mean of AUC_0-24 and C_max were comparable with the values on day 14 across the 3 dose levels.

Implications: OM3-PL/FFA was found to be well tolerated in healthy subjects. The study drug PK properties appeared to be approximately dose proportional over the 1-4 g/d dose range. The bioavailability of OM3-PL/FFA did not appear to be meaningfully affected by the fat content of the meal consumed before dose administration. This is clinically relevant because a low-fat diet is part of the management of patients with HTG.

Keywords: OM3 phospholipids; docosahexaenoic acid; eicosapentaenoic acid; food effect; pharmacokinetics single and multiple doses.