Eicosapentaenoic acid Other names: Timnodonic acid Icosapent

Icosapent ethyl is a stable ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). The mechanisms of action contributing to reduction of cardiovascular events with icosapent ethyl are not completely understood. The mechanisms are likely multi-factorial including improved lipoprotein profile with reduction of triglyceride-rich lipoproteins, anti-inflammatory, and antioxidant effects, reduction of macrophage accumulation, improved endothelial function, increased fibrous cap thickness/stability, and antiplatelet effects. Each of these mechanisms can beneficially alter the development, progression, and stabilisation of atherosclerotic plaque, as well as the implications of plaque rupture, and preclinical and clinical studies support such benefits with EPA. Systemic and localised anti-inflammatory effects of EPA may result from displacement of pro-inflammatory arachidonic acid (AA), directing catabolism away from eicosanoids (2-series prostaglandins and thromboxanes, and 4-series leukotrienes) to non- or anti-inflammatory mediators. However, the direct clinical meaning of individual findings is not clear.

Icosapent ethyl improves the lipoprotein profile by suppressing cholesterol-, fatty acid- and triglyceride (TG)-synthesising enzymes, increasing fatty acid β-oxidation, and reducing microsomal triglyceride transfer (MTP) protein, resulting in decreased hepatic TG and very low-density lipoprotein (VLDL) synthesis and release. Icosapent ethyl also increases expression of lipoprotein lipase leading to increased TG removal from circulating VLDL and chylomicron particles. In patients with elevated TG levels, icosapent ethyl lowers TG, VLDL, remnant lipoprotein cholesterol, and levels of inflammatory markers such as C-reactive protein. However, TG reduction appears to provide only a minor contribution to the reduction in risk of cardiovascular events with icosapent ethyl.

Absorption

After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl.

Icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed.

Distribution

The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.

Biotransformation and elimination

EPA is mainly metabolised by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady-state is 684 mL/hr. The plasma elimination half-life (t_1/2) of EPA is approximately 89 hours. Icosapent ethyl does not undergo renal excretion.

Pharmacokinetic/pharmacodynamic relationship(s)

Triglycerides level/reduction in hypertriglyceridemia

A linear relationship between EPA levels in plasma or red blood cells (RBCs) and TG reduction was observed in two Phase III studies.

Cardiovascular risk reduction

Analyses of the primary (5-point) and key secondary (3-point) MACE endpoints suggest that ontreatment lipoprotein changes had limited influence on cardiovascular risk reductions, while on-treatment steady-state serum EPA levels accounted for the majority of the relative risk reduction observed in REDUCE-IT. Baseline serum EPA level was 26 μg/mL; compared to patients with an ontreatment steady-state serum EPA level below 100 μg/mL, patients with on-treatment EPA levels ≥175 μg/mL had a >50% reduced risk of a cardiovascular event.

Renal and hepatic impairment

The pharmacokinetics of icosapent ethyl has not been studied in patients with renal or hepatic impairment. Patients did not require routine dose adjustment due to hepatic or renal impairment in a well-controlled cardiovascular outcomes study of icosapent ethyl.

Other special populations

Elderly (≥65 years)

The pharmacokinetics of icosapent ethyl has not been studied in elderly patients. Elderly patients did not require routine dose adjustment in well-controlled clinical studies of icosapent ethyl.

Paediatric population

The pharmacokinetics of icosapent ethyl has not been studied in paediatric subjects

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

At the highest dose levels in reproductive and developmental studies, no adverse effects were observed in rats or rabbits at approximately 6 to 8 times the human equivalent dose based on body surface area comparison. In a rat embryo-foetal study, no adverse effects were observed at exposures 6.9 fold higher than the clinical exposure (based on AUC).

Animal studies indicate that icosapent ethyl crosses the placenta and is found in foetal plasma.

Animal studies indicate that icosapent ethyl is excreted in milk.