Abstract 19343: Pharmacokinetic and Triglyceride-Lowering Pharmacodynamic Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) Across Clinical Studies
Background: Icosapent ethyl (IPE; formerly AMR101) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved to reduce triglyceride (TG) levels in patients with severe (>=500 mg/dL) hypertriglyceridemia.
Objective: To examine the effects of IPE on EPA concentrations in plasma and red blood cells (RBCs) in response to dose and the relationship to TG lowering across 3 clinical studies.
Methods: MARINE and ANCHOR were 12-week, phase 3, double-blind studies that randomized patients to IPE 4 g/day, 2 g/day, or placebo. MARINE randomized 229 patients with TG >=500 and <=2000 mg/dL while ANCHOR randomized 702 high-risk patients with TG >=200 and <500 mg/dL despite low-density lipoprotein cholesterol (LDL-C) control while on statin therapy. IPE 4 g/day and 2 g/day was also investigated in 48 healthy subjects for 4 weeks in a phase 1 PK study.
Results: In all studies, a greater increase in EPA concentrations in both plasma and RBCs was observed with IPE 4 g/day than with 2 g/day, indicating a dose-dependent increase in EPA exposure. EPA concentration data from healthy volunteers and in patients with hypertriglyceridemia indicate that the PK of EPA are linear with dose. In MARINE and ANCHOR, median percent reductions in TG from baseline were higher with IPE 4 g/day than with 2 g/day and demonstrated a dose-proportional relationship. In plasma and RBCs, a linear PD relationship between EPA levels and TG reduction was also observed, demonstrating a linear concentration-response relationship. The figure shows TG median % change from baseline versus EPA mean % change from baseline in plasma from the ANCHOR study (error bars are 95% CIs).
Conclusions: Taken together, the linear-dose-PK and dose-concentration-response PD relationships indicate that the PK/PD of IPE are predictable as the results demonstrate a trend of increasing TG-lowering efficacy with respect to both the IPE dose and EPA concentration in plasma and RBCs.
- © 2013 by American Heart Association, Inc.