Omacor Mechanism of Action

Pharmacology: Pharmacodynamics: The omega-3 series polyunsaturated fatty acids (OFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential fatty acids.
They are essential nutrients that cannot be synthesized by the human body in sufficient amounts and have to be obtained in the diet. Like all fatty acids, omega-3 fatty acids are used to provide energy and are stored in adipose tissue; small amounts are incorporated into cell membranes as well.
Omacor is active on the plasma lipids by lowering triglyceride levels as a result of a fall in VLDL (very low density lipoprotein), and the substance is also active on homeostasis and blood pressure.
The mechanism of action of Omacor in lowering plasma triglycerides (TG) is not completely understood. Potential mechanisms of action include inhibition of acyl CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and paroxysmal β-oxidation of fatty acids in the liver and decreased lipogenesis in the liver. Omacor may reduce the synthesis of TG in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.
Omacor increases low density lipoproteins (LDL) cholesterol in some patients with hypertriglyceridaemia.
A small rise in high-density lipoproteins (HDL) cholesterol has also been observed however it is significantly smaller than seen after fibrates, and is not consistent across this population subset.
There is no strong evidence that lowering the triglycerides reduces the risk of ischaemic heart disease.
During treatment with Omacor a decrease in thromboxane A2 production has been observed and a slight increase in bleeding time (particularly with the higher doses, 4 g per day). No significant effect has been observed on the other coagulation factors (see PRECAUTIONS).
Omacor has been shown to cause a significant reduction in blood pressure.
Clinical trials: Hypertriglyceridaemia: There has been eight double-blind, parallel group, placebo-controlled studies in hypertriglyceridaemia, using Omacor 4 g per day. These eight studies are the pivotal studies. These studies included seven individual studies and one part of a study that evaluated Omacor 2 g, 4 g, 8 g, and placebo treatment arms. The duration of the eight pivotal studies was short term (maximum 12 weeks). Numerous studies in patients with hypertriglyceridaemia have been conducted with Omacor, with variable designs: double-blind studies, placebo-controlled studies, randomized studies, open studies and long term studies (up to 24 months). Omacor at doses of 4 g per day consistently and significantly reduced triglycerides levels compared to placebo. The studies have shown that the reductions were maintained for up 24 months after treatment. (See Table 1.)

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The following table summarizes the median percent changes in lipid parameters from baseline in the overall population, and in patients with Types IIb, IV and V dyslipidaemia. (See Table 2.)

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Remarks: The documented number of patients enrolled in clinical trials with Type 1 dyslipidaemia is very limited and no studies were designed to especially investigate the effect of Omacor in these patients. Type HI dyslipidaemic patients are homozygotes for ApoE, and genotyping of patients was only performed in one study (K85-95011). More Type III dyslipidaemic patients may have been therefore enrolled in clinical studies without being verified as such. There is no reason to believe that Type HI dyslipidaemic patients do not respond to Omacor.
One of the pivotal clinical trials in patients with type IV and V (K85-95009 study) demonstrated a mean LDL-C increase of 42.6% with Omacor 4 g per day. 67% of the patients in the study experienced increases in LDL-C, and the increases observed were in the range of 6%-110%. However, mean LDL-C concentrations at the end of the study were still only equal to 2.69 mmol/L (104 mg/dL). For the majority of these patients (40 of 42 with no history of coronary disease) this is still below their target LDL-C levels.
Only equal to 2.69 mmol/L (104 mg/dL).
In clinical trials on patients with Type Hb dyslipidaemia mean LDL-C is unchanged or slightly increased (maximum 8.6%) with Omacor treatment.
In studies with concomitant treatment of Omacor and a statin no significant increase in LDL-C has been observed with Omacor.
The cholesterol enrichment of LDL particles appears to happen in conjunction with a marked reduction in VLDL-C.
Studies also demonstrate a shift from small, dense LDL particles to larger, more buoyant LDL particles, indicating a shift towards less atherogenic lipoprotein particles.
Consistent with the overall population (see Table 3 hereafter), subjects in each baseline triglycerides level category in the Omacor 4 g treatment group had significantly larger mean absolute and relative changes in triglycerides levels compared with those in the placebo treatment group. For the subjects who received Omacor 4 g per day, those with higher baseline levels (TG = 500-749 mg/dL and 3750 mg/dL [5.65-8.46 mmol/L, and 8.47 mmol/L]) had greater reductions in triglycerides levels, and therefore were more likely to exhibit a better response to Omacor. (See Table 3.)

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A number of studies have been conducted to evaluate the effect of concomitant use of Omacor with widely used statins (simvastatin, atorvastatin).
The studies have been carried out in patients with elevated serum triglycerides receiving statin therapy. The results of the studies demonstrate that the combined treatment increases the efficacy in lowering triglycerides. In these studies, little or no effect on LDL-C has been observed and no significant safety issues have been raised.
Pharmacokinetics: The hydrolysis of omega-3 ethyl esters by esterases in the intestine is complete and rapid. After absorption, OFA are metabolised by multiple pathways that are not highly predictable. Animal pharmacokinetic studies have shown that there is no systemic exposure of the ethyl esters. Due to this complicated process, it is not possible to conduct standard bioavailability studies, and consequently, to measure meaningful values for Cmax, Tmax, AUC, etc. for Omacor.
The levels of EPA and DHA do increase on ingestion of Omacor, although in a less than dose proportional manner.
The absorption of Omacor has been determined by measuring the increase of EPA and DHA in plasma serum phospholipids after dosing. Significant, dose-dependent increases in serum phospholipids EPA content were seen, while increase in DHA incorporation were less marked and not dose dependent. Uptake of EPA and DHA into plasma/serum phospholipids in subjects treated with Omacor was also independent of gender, age, and hypertensive status. Concomitant ingestion of another unsaturated fatty acid, olive oil, did not affect absorption of omega-3 fatty acids from Omacor.
During and after absorption there are three main pathways for the metabolism of the omega-3 fatty acids: The fatty acids are first transported to the liver where they are incorporated into various categories of lipoproteins and then channeled to the peripheral lipids stores.
The cell membrane phospholipids are replaced by lipoprotein phospholipids and the fatty acids can then act as precursors for various eicosanoids.
The majority is oxidized to meet energy requirements.
The concentration of omega-3 fatty acids, EPA and DHA, in the plasma phospholipids corresponds to the EPA and DHA incorporated into the cell membranes.