Serum lipid reducing agent/cholesterol and triglycerides reducer/fibrate.
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 α (PPARα).
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 CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously mentioned 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 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 20-25%, triglycerides by 40-55% and HDL cholesterol was increased by 10-30%.
In hypercholesterolemic patients, where LDL cholesterol levels are reduced by 20-35%, 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.
Because of its effect on LDL cholesterol and triglycerides, treatment with fenofibrate should be beneficial in hypercholesterolemic patients with or without hypertriglyceridemia, including secondary hyperlipoproteinemia eg, type 2 diabetes mellitus. At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.
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 eg, C Reactive Protein are reduced with fenofibrate treatment.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidemic patients with hyperuricemia.
Fenofibrate has been shown to possess anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
Pharmacokinetics: Absorption: Maximum plasma concentrations (Cmax) occur within 2-4 hrs after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
In contrast to the other fenofibrate formulations, the maximum plasma concentration and overall exposure of the nanoparticle formulation is independent from food intake. Therefore, Supralip NT 145 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 (>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. 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 hemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hrs.