"Nov. 5, 2012 (Los Angeles) -- An IV infusion of "good" HDL cholesterol seems to rapidly remove cholesterol out of plaque-clogged arteries following a heart attack, a small, early study suggests.
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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 increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-lli (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDLfrom 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 PPARa also induces an increase in the synthesis of apoproteins A-l, A-ll and HDL-cholesterol.
Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
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 Al and apo All) are risk factors 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, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins apo Al and apo All.
Plasma concentrations of fenofibric acid after single-dose administration of Fenoglide (fenofibrate) Tablets, 120 mg are equivalent to those of Fenofibrate 130 mg capsules under high-fat conditions.
A high-fat meal did not affect the fenofibric acid AUC after Fenoglide administration but did increase the mean Cmax by 44% compared to fasting conditions.
The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, Fenoglide is well absorbed from the gastrointestinal tract. 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. Peak plasma levels of fenofibric acid from Fenoglide occur, on average, within 2 to 3 hours after administration.
Doses of three Fenoglide (fenofibrate) Tablets, 40 mg are considered to be equivalent to single doses of Fenoglide (fenofibrate) Tablets, 120 mg.
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.
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 oxidative metabolism (e.g., cytochrome P450) to a significant extent.
After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
Fenofibric acid from Fenoglide is eliminated with a half-life of 23 hours, allowing once daily administration in a clinical setting.
In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of 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.]
Fenoglide has not been investigated in adequate and well-controlled trials in pediatric patients.
No pharmacokinetic difference between males and females has been observed for fenofibrate.
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. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.
The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCI] < 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 (CrCI 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 Fenoglide 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]
No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.
In vitrostudies using human liver microsomes indicate that 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 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]
Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia
The effects of fenofibrate at a dose equivalent to 120 mg Fenoglide 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 therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 2).
Table 2: Mean Percent Change in Lipid Parameters at End
|Mean baseline lipid values (n=646)||306.9 mg/dL||213.8 mg/dL||52.3 mg/dL||191.0 mg/dL|
|All FEN (n=361)||-18.7%*||-20.6%*||+11.0%*||-28.9%*|
|Baseline LDL-C >160 mg/dL and TG <150 mg/dL (Type lla)|
|Mean baseline lipid values (n=334)||307.7 mg/dL||227.7 mg/dL||58.1 mg/dL||101.7 mg/dL|
|All FEN (n=193)||-22.4%*||-31.4%*||+9.8%*||-23.5%*|
|Baseline LDL-C >160 mg/dL and TG >150 mg/dL (Type lib)|
|Mean baseline lipid values (n=242)||312.8 mg/dL||219.8 mg/dL||46.7 mg/dL||231.9 mg/dL|
|All FEN (n=126)||-16.8%*||-20.1%*||+14.6%*||-35.9%*|
|† Duration of study treatment was 3 to 6 months.
* p= <0.05 vs. placebo
In a subset of the subjects, measurements of apo B were conducted. Fenofibrate treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1 % vs. 2.4%, p <O.OOQ1, n=213 and 143 respectively).
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials 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 Fenoglide (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 in Patients With
|Baseline TG levels 350 to 499 mg/dL||N||Baseline (Mean)||Endpoint (Mean)||% Change (Mean)||N||Baseline (Mean)||Endpoint (Mean)||% Change (Mean)|
|Baseline TG levels 500 to 1500 mg/dL||N||Baseline (Mean)||Endpoint (Mean)||% Change (Mean)||N||Baseline (Mean)||Endpoint (Mean)||% Change (Mean)|
|* =p <0.05 vs. placebo|
Last reviewed on RxList: 4/13/2012
This monograph has been modified to include the generic and brand name in many instances.
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