Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red Blood Cells After Multiple Oral Dosing With Icosapent Ethyl in Healthy Subjects.

ABSTRACT

OBJECTIVE: Icosapent ethyl (IPE) is a prescription form of eicosapentaenoic acid (EPA) ethyl ester. This randomized, open-label study characterized EPA pharmacokinetics. METHODS: Four healthy subject groups received IPE for 28 days three received 2 g/day (1 × 1,000 mg BID, 2 × 1,000 mg QD, or 2 × 500 mg BID); one received 4 g/day (2 × 1,000 mg BID) administered with meals. Blood sampling was before the morning dose on days 1, 14, 26, 28, and at specified intervals during an 18-day pharmacokinetic period. EPA was measured in plasma (total and unesterified) and red blood cells (RBCs) by liquid chromatography/tandem mass spectrometry. RESULTS: Mean plasma total EPA increased from 19 µg/mL to a peak (Cmax) of 366 µg/mL at 5 hours postdosing 4 g/day IPE on Day 28. Mean RBC EPA Cmax after 4 g/day was 89 µg/mL (baseline, 12 µg/mL). Mean steady state (SD) for half-life, clearance, and volume of distribution of total EPA were 79 (47) hours, 757 (283) mL/h, and 82 (56) L, respectively. Steady state for total and unesterified plasma EPA was reached by Day 28, whereas RBC levels were still increasing. CONCLUSIONS: EPA pharmacokinetic profile demonstrated a slowly cleared, extensively distributed molecule with dose linearity and comparable exposures with BID and QD regimens.