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Pharmacology: Pharmacodynamics: Mechanism of Action: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are medicated via activation of peroxisome proliferated receptor type α (PPAR). Through activation of PPAR, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides (TGs) produces an alteration in the size and composition of low density lipoprotein (LDL) from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. Those larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins AI and AII and high density lipoprotein (HDL) cholesterol.
The previously stated effects of fenofibrate on lipoproteins leads to a reduction in very low density fractions (VLDL and LDL) containing apoprotein AI and AII (Apo I and Apo II).
In addition, through modulation of 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.
Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
Clinical Studies: 160-mg: During clinical trials with fenofibrate, total-C was reduced by 20-25%, triglycerides by 40-55% and HDL-cholesterol (HDL-C) was increased by 10-30%.
In hypercholesterolaemic patients, where LDL-cholesterol (LDL-C) levels are reduced by 20-35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol (total-C) to HDL-C, LDL-C to HDL-C, or apoprotein B (Apo B) to Apo AI, all of which are markers of atherogenic risk. Because of its significant effect on LDL-C and TGs, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients, with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia eg, type 2 diabetes mellitus.
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 lipoprotein (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 dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an 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. The effect of fenofibrate on coronary heart disease morbidity and non-cardiovascular mortality has not been established.
Pharmacokinetics: 145-mg: Plasma concentrations of fenofibric acid after administration one 145-mg tablet is equivalent under fed conditions to 1 micronized fenofibrate 200 mg capsule.
Fenofibrate is a prodrug of the active chemical moiety fenofibric acid. It is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.
Absorption: Fenofibrate is well-absorbed from the gastrointestinal tract. Peak plasma levels of fenofibric acid occur within 6-8 hrs after administration.
145-mg: Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate and 25% was excreted in the feces.
Exposure to fenofibric acid in plasma, as measured by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) is not significantly different when a single fenofibrate 145 mg dose is administered under fasting or nonfasting conditions.
160-mg: The absorption of fenofibrate tablets is increased by approximately 35% under fed as compared to fasting conditions.
Distribution: Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
145-mg: Upon multiple dosing of fenofibrate, fenofibric acid steady-state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady-state are approximately double of those following a single dose.
160-mg: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing and did not demonstrate accumulation across time following multiple dose administration.
Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid, no unchanged fenofibrate is detected in plasma.
Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidate metabolism (eg, cytochrome P450) to a significant extent.
Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide.
145-mg: After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 26% was excreted in the feces.
Fenofibric acid is eliminated with a half-life (t½) of 20 hrs, allowing once daily dosing.
160-mg: Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in the urine, primarily as fenofibric acid and its glucuronate conjugate and 25% was excreted in the feces. Fenofibric acid is eliminated with a t½ of 20 hrs, allowing once-daily administration in a clinical setting.
Special Populations: Elderly: In elderly volunteers 77-87 years, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/hr, which compares to 1.1 L/hr in young adults. This indicates that a similar dosage regimen can be used in elderly with normal renal function, without increasing accumulation of Colestrim/Colestrim Supra or metabolites.
Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied. However, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal Impairment: 145-mg: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2] showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) had similar exposure but an increase in the t½ for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Colestrim Supra should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.
160-mg: In patients with severe renal impairment [creatinine clearance (CrCl) <500 mL/min] the rate of clearance of fenofibric acid is greatly reduced and the drug accumulated during chronic dosage. However, in patients having moderate renal impairment (CrCl <50-90 mL/min). The oral clearance and oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/hr and 95 L versus 1.1 L/hr and 30 L, respectively). Therefore, the dosage of fenofibrate should be minimized in patients who have severe renal impairment, while no modification is required in patients having moderate renal impairment.
Hepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.
