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Mechanism of Action

The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα).

Through this mechanism, fenofibrate (fenofibrate (fenofibrate) ) increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I,A-II and HDL-cholesterol.

Fenofibrate (fenofibrate (fenofibrate) ) also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are risk factor for the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate (fenofibrate (fenofibrate) ) , produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate (fenofibrate (fenofibrate) ) results in increases in high density lipoprotein (HDL) and apoproteins apo AI and apo AII.

Pharmacokinetics

Plasma concentrations of fenofibric acid after single-dose administration of Fenofibrate Tablets, 120 mg are equivalent to those of Fenofibrate (fenofibrate (fenofibrate) ) 130 mg capsules under high-fat conditions.

A high-fat meal did not affect the fenofibric acid AUC after Fenofibrate (fenofibrate (fenofibrate) ) Tablets administration but did increase the mean Cmax by 44% compared to fasting conditions.

• Absorption: The absolute bioavailability of fenofibrate (fenofibrate (fenofibrate) ) cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate (fenofibrate (fenofibrate) ) is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate (fenofibrate (fenofibrate) ) appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate (fenofibrate (fenofibrate) ) occur, on average, within 2 to 3 hours after administration.
  • Doses of three Fenofibrate (fenofibrate (fenofibrate) ) Tablets, 40 mg are considered to be equivalent to single doses of Fenofibrate (fenofibrate (fenofibrate) ) Tablets, 120 mg.
• Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
• Metabolism: Following oral administration, fenofibrate (fenofibrate (fenofibrate) ) is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate (fenofibrate (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 (fenofibrate (fenofibrate) ) nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
• Excretion: After absorption, fenofibrate (fenofibrate (fenofibrate) ) is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate (fenofibrate (fenofibrate) ) , approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
  • Fenofibrate acid from Fenofibrate (fenofibrate (fenofibrate) ) Tablets is eliminated with a half-life of 23 hours, allowing once daily administration in a clinical setting.
• Geriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate (fenofibrate (fenofibrate) ) was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites. [See Dosage and Administration and Use in Specific Populations.]
• Pediatrics: Fenofibrate (fenofibrate (fenofibrate) ) has not been investigated in adequate and well-controlled trials in pediatric patients.
• Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate (fenofibrate (fenofibrate) ) .
• Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate (fenofibrate (fenofibrate) ) is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.
• Renal Insufficiency: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] ≤ 30 mL/min or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m²) 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 (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m²) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate (fenofibrate (fenofibrate) ) should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment. [See Dosage and Administration.]
• Hepatic Insufficiency: No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.
• Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate (fenofibrate (fenofibrate) ) and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
  • Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR. [See Concomitant Coumarin Anticoagulants.]
  • Bile-acid resins have been shown to bind other drugs given concurrently. Therefore, fenofibrate (fenofibrate (fenofibrate) ) should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. [See Drug Interactions.]

Clinical Studies

Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

The effects of fenofibrate at a dose equivalent to 120 mg fenofibrate (fenofibrate (fenofibrate) ) per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate (fenofibrate (fenofibrate) ) therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate (fenofibrate (fenofibrate) ) therapy also lowered triglycerides and raised HDL-C (see Table 2).

Table 2. Mean Percent Change in Lipid Parameters at End of Treatment^†

In a subset of the subjects, measurements of apo B were conducted. Fenofibrate (fenofibrate (fenofibrate) ) treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively).

Hypertriglyceridemia

The effects of fenofibrate (fenofibrate (fenofibrate) ) on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials¹ of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 120 mg Fenofibrate (fenofibrate (fenofibrate) ) Tablets per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 3).

Table 3. Effects of Fenofibrate (fenofibrate (fenofibrate) ) in Patients With Hypertriglyceridemia

Last reviewed on RxList: 9/7/2007
This monograph has been modified to include the generic and brand name in many instances.