Lipanthyl Penta 145

Lipanthyl Penta 145 Mechanism of Action





Zuellig Pharma
Full Prescribing Info
Serum Lipid Reducing Agents / Cholesterol and Triglycerides Reducers / Fibrates. ATC code: C10 AB 05.
Pharmacology: Pharmacodynamics: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPAR∝). Through activation of PPARα, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The above stated effects of fenofibrate on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
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 hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol 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 they have 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 of 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic 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) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Another prespecified 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 outcome in women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia 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 xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate treatment.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals andin a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
Effects of fenofibrate on the reduction of the progression of microvascular complications in patients with type 2 of diabetes mellitus have been proven in international randomized placebo-controlled trials.
In the ACCORD trial (in a subgroup of 1953 patients, ACCORD-eye substudy) the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale was 6.5% with fenofibrate and simvastatin combined with dyslipidemia therapy, versus 10.2% with simvastatin and placebo therapy (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006).
Fenofibrate therapy was also associated with lower frequency of laser treatment required for retinopathy (5.2% vs 3.6%, p=0.0003) in the FIELD study.
Pharmacokinetics: LIPANTHYL PENTA 145 mg, film-coated tablets contains 145 mg of fenofibrate nanoparticles.
Absorption: Maximum plasma concentrations (Cmax) occur within 2 to 4 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall exposure of the nanoparticle formulation is independent from food intake. Therefore, LIPANTHYL PENTA 145, film-coated tablet may be taken without regard to meals.
A food-effect study involving administration of the new 145 mg tablet formulation of fenofibrate to healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and Cmax) to fenofibric acid is not affected by food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and excretion: After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. 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. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug 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: Acute toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
In a three-month oral nonclinical study in the rat species with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I - slow oxidative- myofibres) and cardiac degeneration, anemia and decreased body weight were seen at exposure levels ≥50- fold the human exposure for the skeletal toxicity and >15 fold for the cardiomyotoxicity.
Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated during 3 months at exposures approximately 7-fold the clinical AUC.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours 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 man.
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.
No effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate. However reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs.
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