Lipanthyl Penta 145 Mechanism of Action

Pharmacotherapeutic group: lipid lowering agents/cholesterol and triglyceride lowering products/fibrates. ATC code: C10AB05.
Pharmacology: Pharmacodynamics: Fenofibrate is a fibric acid derivative whose lipid-regulating effects in humans are mediated via activation of PPARα (peroxisome proliferator activated receptor type alpha).
Activation of PPARα increases the activity of lipoprotein lipase and reduces the production of apoliprotein CIII. Via this mechanism, fenofibrate raises lipolysis and elimination of atherogenic, triglyceride-rich particles from the plasma. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously mentioned effects of fenofibrate lead to a reduction in very-low-density and low-density lipoproteins (VLDL and LDL) containing apolipoprotein B and an increase in the high-density lipoproteins (HDL) due to increased production of apoproteins AI and AII.
Patients with an elevated CHD (coronary heart disease) risk commonly express an atherogenic liporotein phenotype characterized by an increased fraction of small dense LDL particles. By regulating the synthesis and catabolism of VLDL, fenofibrate lowers the levels of small dense LDL and increases LDL clearance.
During clinical trials with fenofibrate, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol (LDL, HDL) results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or apo B to apo AI, all of which are markers of atherogenic risk.
There is evidence that treatment with fibrates may reduce coronary heart disease events but it has not been shown to decrease all-cause mortality in the primary or secondary prevention of cardiovascular disease.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study in 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Treatment with fenofibrate plus simvastatin did not show significant differences in the composite primary endpoint of non-fatal myocardial infarction, non-fatal stroke and cardiovascular deaths compared to simvastatin monotherapy (hazard ratio [HR] 0.92; 95% Cl: 0.79 to 1.08; p=0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidemic patients, defined as those in the lowest tertile of HDL-C (≤34 mg/dL or 0.88 mmol/L) and highest tertile of TG (≥204 mg/dL or 2.3 mmol/L), fenofibrate plus simvastatin therapy demonstrated a 31% relative risk reduction compared to simvastatin monotherapy for the composite primary outcome criterion (Hazard Ratio [HR] 0.69; 95% Cl 0.49 to 0.97; p=0.03; absolute risk reduction: 4.95%). Another pre-specified subgroup analysis identified a statistically significant treatment-by-gender interaction (p=0.01) indicating a possible treatment benefit of combination therapy in men (p=0.037) but a potentially higher risk for the primary endpoint in women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the previously mentioned subgroup of patients with dyslipidemia, but there was also no clear evidence of benefit in dyslipidaemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Extravascular deposits of cholesterol (tendinous and tuberous xanthomas) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
In patients with elevated baseline Lp(a) or fibrinogen levels, treatment with fenofibrate produced a significant lowering of Lp(a) or fibrinogen concentrations. Other inflammatory markers such as C-reactive protein are reduced with fenofibrate treatment.
Fenofibrate produces an approximately 25% reduction of uric acid levels. This is of additional benefit in dyslipidaemic patients with hyperuricaemia.
In animal studies and a clinical trial, fenofibrate inhibited platelete aggregation induced by ADP, arachidonic acid and epinephrine.
Pharmacokinetics: LIPANTHYL PENTA 145 contains 145 mg of fenofibrate as nanoparticles in the form of a film-coated tablet.
Absorption: Maximum plasma concentrations (C_max) occur within 2-4 hours after oral administration. Plasma concentrations remain constant in any given individual following repeated administration.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall exposure of the nanoparticle formation is independent from food intake. Therefore, the medicinal product may be taken without regard to meals.
A study involving healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and C_max) to fenofibric acid is not affected by food.
Distribution: Fenofibric acid is strongly bound to plasma albumin >99%).
Metabolism and excretion: After oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP3A4. No hepatic microsomal metabolism is involved.
The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. Plasma clearance of fenofibric acid is unchanged in the elderly patients.
Pharmacokinetic studies with single and repeated dosing have demonstrated that the active substance does not accumulate. Fenofibric acid is not eliminated by haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Toxicology: Preclinical safety data: In a three-month, oral, non-clinical study in rats with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I fibres) and heart failure, anaemia and decreased body weight were seen. No skeletal toxicity was noted at doses up to 30 mg/kg [approximately 17 times the maximum recommended human dose (MRHD)]. No signs of cardiac toxicity were noted at approximately three times the MRHD.
Reversible ulcers and erosions in the gastrointestinal tract occurred in dogs treated for three months. No gastrointestinal lesions were noted in this study at approximately five times the MRHD.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumors have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in humans.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. Reversible hypospermia, testicular vasculation and immaturity of the ovaries were observed in a repeat-dose study with fenofibric acid in young dogs. However, no effect on fertility were detected in preclinical reproductive studies with fenofibrate.