Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects

摘要

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 2g/day (1×1,000mg BID, 2×1,000mg QD, or 2×500mg BID); one received 4g/day (2×1,000mg 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 19μg/mL to a peak (Cmax) of 366μg/mL at 5hours postdosing 4g/day IPE on Day 28. Mean RBC EPA Cmax after 4g/day was 89μg/mL (baseline, 12μg/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.