TriCor - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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TriCor - Scientific Information

Manufacture: AbbVie
Country: United States
Condition: Hypertriglyceridemia, Hyperlipoproteinemia Type V, Elevated Chylomicrons VLDL, Hyperlipoproteinemia Type IV, Elevated VLDL, Hyperlipoproteinemia Type IIb, Elevated LDL VLDL, Hyperlipoproteinemia Type IIa, Elevated LDL, Hyperlipoproteinemia
Class: Fibric acid derivatives
Form: Tablets
Ingredients: Fenofibrate

Description

TRICOR (fenofibrate tablets), is a lipid regulating agent available as tablets for oral administration. Each tablet contains 48 mg or 145 mg of fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:

The empirical formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82°C. Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive Ingredients

Each tablet contains hypromellose 2910 (3 cps), docusate sodium, sucrose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone, and magnesium stearate.

In addition, individual tablets contain:

48 mg tablets

polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, xanthan gum, D&C Yellow #10 aluminum lake, FD&C Yellow #6 /sunset yellow FCF aluminum lake, FD&C Blue #2 /indigo carmine aluminum lake.

145 mg tablets

polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, xanthan gum.

Clinical Pharmacology

Mechanism of Action

The active moiety of TRICOR is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.

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 approtein C-III (an inhibitor of lipoprotein lipase activity).

The resulting decrease in TG 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 apolipoproteins A-I, A-II and HDL-cholesterol.

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-C, LDL-C, and apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, 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 apolipoproteins apoAI and apoAII.

Pharmacokinetics

Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule.

Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.

Absorption

The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate 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 occur within 6 to 8 hours after administration.

Exposure to fenofibric acid in plasma, as measured by Cmax and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.

Distribution

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. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

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 oxidative metabolism (e.g., 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. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing.

Special Populations

Geriatrics

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 elderly with normal renal functoin, without increasing accumulation of the drug or metabolites [see Dosage and Administration and Use in Specific Populations].

Pediatrics

The pharmacokinetics of TRICOR has not been studied in pediatric populations.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

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

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) 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 (CrCl 50–80 mL/min) to moderate (CrCl 30-50 mL/min) renal impairment 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 TRICOR 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 Impairment

No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.

Drug-drug Interactions

In vitro studies 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 CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Table 1 describes the effects of co-administered drugs on fenofibric acid systemic exposure.

Table 2 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs.

Table 1. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure
  AUC Cmax
Lipid-lowering agents
Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg1 once daily for 10 days ↓2% ↓4%
Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg2 as a single dose ↓1% ↓2%
Fluvastatin 40 mg as a single dose Fenofibrate 160 mg1 as a single dose ↓2% ↓10%
Anti-diabetic agents
Glimepiride 1 mg as a single dose Fenofibrate 145 mg1 once daily for 10 days ↓1% ↓1%
Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg1 three times daily for 10 days ↓9% ↓6%
Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg1 once daily for 14 days ↓10% ↓3%
1 TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule

Table 3. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure
  Analyte AUC Cmaxsub>
Lipid-lowering agents
Fenofibrate 160 mg1 once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0%
Fenofibrate 3 x 67 mg2 as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13%
    3α-Hydroxyl-iso-pravastatin ↑26% ↑29%
Fenofibrate 160 mg1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16%
Anti-diabetic agents
Fenofibrate 145 mg1 once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18%
Fenofibrate 54 mg1 three daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin ↑3% ↑6%
Fenofibrate 145 mg1 once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1%
1 TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Mutagenesis

Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.

Impairment of Fertility

In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons).

Clinical Studies

Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

The effects of fenofibrate at a dose equivalent to 145 mg TRICOR (fenofibrate tablets) 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. TRICOR therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. TRICOR therapy also lowered triglycerides and raised HDL-C (see Table 3).

Table 3. Mean Percent Change in Lipid Parameters at End of Treatment†
Treatment Group Total-C LDL-C HDL-C TG
Pooled Cohort
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%*
Placebo (n=285) -0.4% -2.2% +0.7% +7.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL
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%*
Placebo (n=141) +0.2% -2.2% +2.6% +11.7%
Baseline LDL-C >160 mg/dL and TG ≥ 150 mg/dL
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%*
Placebo (n=116) -3.0% -6.6% +2.3% +0.9%

† 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. TRICOR 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).

Severe Hypertriglyceridemia

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 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 TRICOR 145 mg 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 LDL-C (see Table 4).

Table 4. Effects of TRICOR in Patients With Severe Hypertriglyceridemia
Study 1 Placebo TRICOR
Baseline TG levels 350 to 499 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean)
Triglycerides 28 449 450 -0.5 27 432 223 -46.2*
VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1*
Total Cholesterol 28 255 261 2.8 27 252 227 -9.1*
HDL Cholesterol 28 35 36 4 27 34 40 19.6*
LDL Cholesterol 28 120 129 12 27 128 137 14.5
VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7*
Study 2 Placebo TRICOR
Baseline TG levels 500 to 1500 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean)
Triglycerides 44 710 750 7.2 48 726 308 -54.5*
VLDL Triglycerides 29 537 571 18.7 33 543 205 -50.6*
Total Cholesterol 44 272 271 0.4 48 261 223 -13.8*
HDL Cholesterol 44 27 28 5.0 48 30 36 22.9*
LDL Cholesterol 42 100 90 -4.2 45 103 131 45.0*
VLDL Cholesterol 42 137 142 11.0 45 126 54 -49.4*

* =p < 0.05 vs. Placebo

The effect of TRICOR on cardiovascular morbidity and mortality has not been determined.