Source: FDA, National Drug Code (US) Revision Year: 2020
The active moiety of Trilipix 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 peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity).
Activation of PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII.
Trilipix contains fenofibric acid, which is the only circulating pharmacologically active moiety in plasma after oral administration of Trilipix. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid.
Plasma concentrations of fenofibric acid after administration of one 135 mg Trilipix delayed release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions.
Fenofibric acid is well absorbed throughout the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%.
Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of Trilipix capsule under fasting conditions.
Fenofibric acid exposure in plasma, as measured by Cmax and AUC, is not significantly different when a single 135 mg dose of Trilipix is administered under fasting or nonfasting conditions.
Upon multiple dosing of Trilipix, fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum protein binding is approximately 99% in normal and dyslipidemic subjects.
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 after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
After absorption, Trilipix is primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide.
Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once daily administration of Trilipix.
In five 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 an equivalent dose of Trilipix can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5)].
The pharmacokinetics of Trilipix has not been studied in pediatric populations.
No pharmacokinetic difference between males and females has been observed for Trilipix.
The influence of race on the pharmacokinetics of Trilipix has not been studied; however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability.
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/1.73m²) showed a 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/1.73m²) 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 Trilipix 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 (2.4)].
No pharmacokinetic studies have been conducted in patients with hepatic impairment.
In vitro studies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. It is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations.
Comparison of atorvastatin exposures when atorvastatin (80 mg once daily for 10 days) is given in combination with fenofibric acid (Trilipix 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The Cmax decreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for parahydroxy-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and orthohydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin.
Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (Trilipix 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The Cmax increased by 26% and 7% for total and free ezetimibe, respectively. The AUC increased by 27% and 12% for total and free ezetimibe, respectively.
Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibric acid on other drugs.
Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Trilipix or Fenofibrate Administration:
| Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Trilipix or Fenofibrate | Changes in Fenofibric Acid Exposure | |
|---|---|---|---|---|
| AUC | Cmax | |||
| Lipid-lowering agents | ||||
| Rosuvastatin | 40 mg once daily for 10 days | Trilipix 135 mg once daily for 10 days | ↓2% | ↓2% |
| Atorvastatin | 20 mg once daily for 10 days | Fenofibrate 160 mg1 once daily for 10 days | ↓2% | ↓4% |
| Atorvastatin + ezetimibe | Atorvastatin, 80 mg once daily and ezetimibe, 10 mg once daily for 10 days | Trilipix 135 mg once daily for 10 days | ↑5% | ↑5% |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 × 67 mg2 as a single dose | ↓1% | ↓2% |
| Fluvastatin | 40 mg as a single dose | Fenofibrate 160 mg1 as a single dose | ↓2% | ↓10% |
| Simvastatin | 80 mg once daily for 7 days | Fenofibrate 160 mg1 once daily for 7 days | ↓5% | ↓11% |
| Anti-diabetic agents | ||||
| Glimepiride | 1 mg as a single dose | Fenofibrate 145 mg1 once daily for 10 days | ↑1% | ↓1% |
| Metformin | 850 mg 3 times daily for 10 days | Fenofibrate 54 mg1 3 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% |
| Gastrointestinal agents | ||||
| Omeprazole | 40 mg once daily for 5 days | Trilipix 135 mg as a single dose fasting | ↑6% | ↑17% |
| Omeprazole | 40 mg once daily for 5 days | Trilipix 135 mg as a single dose with food | ↑4% | ↓2% |
1 TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule
Table 3. Effects of Trilipix or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs:
| Dosage Regimen of Trilipix or Fenofibrate | Dosage Regimen of Co-Administered Drug | Change in Co-Administered Drug Exposure | ||
|---|---|---|---|---|
| Analyte | AUC | Cmax | ||
| Lipid-lowering agents | ||||
| Trilipix 135 mg once daily for 10 days | Rosuvastatin, 40 mg once daily for 10 days | Rosuvastatin | ↑6% | ↑20% |
| Fenofibrate 160 mg1 once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓17% | 0% |
| Fenofibrate 3 × 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% |
| Fenofibrate 160 mg1 once daily for 7 days | Simvastatin, 80 mg once daily for 7 days | Simvastatin acid | ↓36% | ↓11% |
| Simvastatin | ↓11% | ↓17% | ||
| Active HMG-CoA Inhibitors | ↓12% | ↓1% | ||
| Total HMG-CoA Inhibitors | ↓8% | ↓10% | ||
| Anti-diabetic agents | ||||
| Fenofibrate 145 mg1 once daily for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑35% | ↑18% |
| Fenofibrate 54 mg1 3 times daily for 10 days | Metformin, 850 mg 3 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
No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either Trilipix or fenofibrate.
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) of 300 mg fenofibrate daily, equivalent to 135 mg Trilipix daily, based on body surface area comparisons. 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, based on body surface area comparisons), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m 2 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, based on body surface area comparisons) 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.
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.
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 body surface area comparisons).
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 135 mg once daily of Trilipix decreased primarily VLDL-TG and VLDL-C. Treatment of patients with elevated TG often results in an increase of LDL-C (Table 4).
Table 4. Effects of Fenofibrate in Patients With Severe Hypertriglyceridemia:
| Study 1 | Placebo | Fenofibrate | ||||||
|---|---|---|---|---|---|---|---|---|
| Baseline TG levels 350 to 499 mg/dL | N | Baseline Mean (mg/dL) | Endpoint Mean (mg/dL) | Mean % Change | N | Baseline Mean (mg/dL) | Endpoint Mean (mg/dL) | Mean % Change |
| 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 | Fenofibrate | ||||||
| Baseline TG levels 500 to 1500 mg/dL | N | Baseline Mean (mg/dL) | Endpoint Mean (mg/dL) | Mean % Change | N | Baseline Mean (mg/dL) | Endpoint Mean (mg/dL) | Mean % Change |
| 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 effects of fenofibrate at a dose equivalent to Trilipix 135 mg once daily 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 (Table 5).
Table 5. Mean Percent Change in Lipid Parameters at End of Treatment†:
| Treatment Group | Total-C (mg/dL) | LDL-C (mg/dL) | HDL-C (mg/dL) | TG (mg/dL) |
|---|---|---|---|---|
| Pooled Cohort | ||||
| Mean baseline lipid values (n=646) | 306.9 | 213.8 | 52.3 | 191.0 |
| All Fenofibrate (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 | 227.7 | 58.1 | 101.7 |
| All Fenofibrate (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 | 219.8 | 46.7 | 231.9 |
| All Fenofibrate (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. 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).
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