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Trilipix

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Trilipix




CLINICAL PHARMACOLOGY

Mechanism Of Action

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.

Pharmacokinetics

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.

Absorption

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.

Distribution

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.

Metabolism

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.

Elimination

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.

Specific Populations

Geriatrics

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].

Pediatrics

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

Gender

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

Race

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.

Renal Impairment

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].

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment.

Drug-drug Interactions

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 parahydroxyatorvastatin. 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 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%
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%
1TriCor (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 C max
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 x 67 mg2 as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13%
3a-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%
1TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule

Clinical Studies

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 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

Primary Hypercholesterolemia (Heterozygous Familial And Nonfamilial) And Mixed Dyslipidemia

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).

Last reviewed on RxList: 5/11/2015
This monograph has been modified to include the generic and brand name in many instances.

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