CLINICAL PHARMACOLOGY
Mechanism of Action
The active moiety of Triglide is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.
The lipid-modifying 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 perxisome proliferators 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-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 artherogenic 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 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 TC, 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 TC, LDL-C, and triglycerides (TG), and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering 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 AI and apo AII.
Pharmacokinetics
Triglide 160 mg tablet was shown to have comparable bioavailability to a single dose of 200 mg fenofibrate capsule, micronized. 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. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, 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 an average of 3 hours after administration. The extent of absorption of Triglide (AUC) is comparable between fed and fasted conditions. Food increases the rate of absorption of Triglide approximately 55%.
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 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.
E
limination: 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 approximately 16 hours, allowing once daily dosing.
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 the elderly, without increasing accumulation of the drug or metabolites. [See
Dosage and Administration
and
Use in Specific Populations
.]
Pediatrics: Pharmacokinetics of Triglide has not been studied in pediatric patients.
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] < 30 mL/min or 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 (CrCl 30-80 mL/min or eGRF 30-59 mL/min/1.73 m2) 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 Triglide 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
I
mpairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment.
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 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure.
Table 3 describes the effects of fenofibrate on co-administered drugs.
Table 2. 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 on Systemic Exposure of Co-Administered Drugs
Dosage Regimen of
Fenofibrate
|
Dosage Regimen of
Co-Administered Drug
|
|
Change in Co-Administered Drug Exposure
|
|
|
| Analyte |
| AUC |
Cmax
|
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 times 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
Carcinogenesis: 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 MRHD), the incidence of liver carcinoma 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 in males at 6 times the MRHD. In a second 24-month 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; 2 times the human dose), and gemfibrozil (250 mg/kg; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinomas 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 (approximately 10 times the MRHD, based on mg/m2 surface area comparisons).
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