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Trilipix

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Trilipix

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).

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 HDL-C and Apo AI and AIL

Pharmacodynamics

Elevated levels of Total-C, LDL-C, and Apo B, and decreased levels of HDL-C and its transport complex,

Apo AI and Apo All, are risk factors for human atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the levels of Total-C, LDL-C, and 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 TC, LDL-C, Apo B, TG, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibric acid results in increases in HDL-C and Apo AI and Apo AIL

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 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 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on other drugs.

Table 3: 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 ↓1% ↓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 15% ↓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%
1TnCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule

Table 4: 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 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 ↑l5% ↑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 mg1once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18%
Fenofibrate 54 mg13 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

Clinical Studies

Co-Administration Therapy with Statins

Efficacy and safety of Trilipix co-administered with statins were assessed in three 12-week, double-blind, controlled Phase 3 studies and one 52-week, long-term, open-label extension study in 2698 patients with mixed dyslipidemia. Patients were required to meet the following fasting lipid entry criteria: TG ≥ 150 mg/dL, and HDL-C < 40 mg/dL (males) and < 50 mg/dL (females), and LDL-C ≥ 130 mg/dL. The three multicenter, randomized, double-blind, controlled studies had similar designs, differing primarily in the statin used for combination therapy/monotherapy. Each study compared the effects of 135 mg Trilipix co-administered with either a low dose or a moderate dose of statin with Trilipix monotherapy and statin monotherapy at the corresponding dose on CHD lipid risk factors. A smaller group of patients received a high dose of statin monotherapy. In study 1, patients received Trilipix co-administered with 10 mg or 20 mg rosuvastatin. In study 2, patients received Trilipix co-administered with 20 mg or 40 mg simvastatin. In study 3, patients received Trilipix co-administered with 20 mg or 40 mg atorvastatin.

Patients were enrolled for a total of approximately 22 weeks, consisting of a 6-week diet run-in/washout period, a 12-week treatment period, and a 30-day safety follow up period. Patients who completed the 12-week treatment period were eligible to participate in the 52-week long-term extension study. Of the 2698 randomized and treated subjects in the controlled studies, 51.6% were female and 48.4% were male; 92.6% of all subjects were White, 4.7% were Black, and 2.8% were of other races. Hispanics comprised 9.9% of the study population. Mean age was 54.9 years.

The primary efficacy endpoints for all three studies were mean percent changes from baseline to final value in HDL-C, TG, and LDL-C. For each statin dose co-administered with Trilipix, there were three primary comparisons. For HDL-C and TG, Trilipix co-administered with each statin dose was compared with statin monotherapy at the corresponding dose. For LDL-C, Trilipix co-administered with each statin dose was compared with Trilipix monotherapy. In order to declare combination therapy successful for a particular statin dose, all three primary comparisons were required to demonstrate superiority of the combination therapy over the corresponding monotherapy. The primary efficacy results were consistent in the three studies and were confirmed by the pooled analysis of the three studies. The results from the individual studies and the pooled analysis demonstrated that Trilipix co-administered with low-dose statins and moderate-dose statins was superior to the corresponding monotherapy. Statistically significant differences were observed for all three primary efficacy comparisons for both doses of combination therapy in all three double-blind, controlled studies as well as the pooled analysis.

In the pooled analysis, Trilipix co-administered with both low-dose statins and moderate-dose statins resulted in mean percent increases (18.1% and 17.5%) in HDL-C and mean percent decreases (-43.9% and -42.0%) in TG that were significantly greater than the corresponding dose of statin monotherapy (7.4% and 8.7% for HDL-C; -16.8% and -23.7% for TG). In addition, both doses of combination therapy resulted in mean percent decreases (-33.1% and -34.6%) in LDL-C that were significantly greater than Trilipix monotherapy (-5.1%). The results of the pooled analysis are described in Table 5.

Table 5: Mean Percent Change from Baseline to the Final Value in HDL-C, TG, and LDL-C (Pooled Double-Blind, Controlled

  Trilipix Low-Dose Statin Trilipix + Low-Dose Statin Between-group A (p-value) Moderate-Dose Statin Trilipix + Moderate-Dose Statin Between-group Δ (p-value) High-Dose Statin
HDL-C (mg/dL) (N = 420) (N = 455) (N = 423)   (N = 430) (N = 422)   (N = 217)
BL mean 38.4 38.4 38.2   38.4 38.1   38.0
Mean % Δ 16.3% 7.4% 18.1% 10.7%a (< 0.001) 8.7% 17.5% 8.8%a ( < 0.001) 7.9%
TG (mg/dL) (N = 459) (N = 477) (N = 470)   (N = 472) (N = 462)   (N = 235)
BL mean 280.7 286.1 282.1   287.9 286.1   282.5
Mean % Δ -31.0% -16.8% -43.9% -27.2%a ( < 0.001) -23.7% -42.0% -18.3%a ( < 0.001) -28.1%
LDL-C (mg/dL) (N = 427) (N = 463) (N = 436)   (N = 439) (N = 434)   (N = 225)
BL mean 158.4 153.8 155.7   158.0 156.4   156.1
Mean % Δ -5.1% -33.9% -33.1% -28.0%b ( < 0.001) -40.6% -34.6% -29.5%b ( < 0.001) -47.1%
a Combination therapy vs. corresponding statin monotherapy
b Combination therapy vs. Trilipix monotherapy
Low-dose statin = rosuvastatin 10 mg, simvastatin 20 mg, or atorvastatin 20 mg
Moderate-dose statin = rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg
High-dose statin = rosuvastatin 40 mg, simvastatin 80 mg, or atorvastatin 80 mg
BL = Baseline
% Δ = Percent change from baseline to final value

Secondary efficacy endpoints in all three double-blind, controlled studies were percent changes in non-HDL-C (Trilipix co-administered with statin compared to Trilipix monotherapy and corresponding statin monotherapy), and percent changes in VLDL-C, Total-C, and Apo B (Trilipix co-administered with statin compared to corresponding statin monotherapy). Co-administration of Trilipix with statins resulted in the following changes in secondary parameters (Table 6).

Table 6: Percent Change from Baseline to the Final Value in Non-HDL-C, VLDL-C, Total-C, and Apo B (Pooled Double, Blind, Controlled Studies)

Secondary Endpoints Trilipix Low-Dose Statin Trilipix + Low-Dose Statin Between-group Δ Moderate-Dose Statin Trilipix + Moderate-Dose Statin Between-group Δ High-Dose Statin
Non HDL-C (mg/dL) (N = 420) (N = 454) (N = 422)   (N = 431) (N = 420)   (N = 217)
BL mean 222.5 217.6 219.9   222.4 218.9   220.2
Mean %Δ -17.3% -34.9% -40.4% -23.1 %a -5.5%b -42.4% -42.0% -24.8%a 0.4%b -47.3%
VLDL-C (mg/dL) (N 449) (N = 463) (N = 455)   (N =458) (N=449)   (N = 232)
BL mean 65.0 66.0 65.5   67.8 64.5   66.1
     
Mean %Δ -34.2% -32.1% -50.0% -18.0%b -38.9% -51.2% -12.3%b -42.1%
Total-C (mg/dL) (N = 459) (N = 477) (N = 469)   (N = 472) (N = 462)   _JN = 235)
BL mean 260.9 257.0 258.6   261.3 257.3   258.8
Mean % Δ -12.4% -28.7% -31.5% -2.8%b -34.7% -33.3% 1.4%b -39.5%
Apo B (mg/dL) (N = 455) (N = 470) (N = 465)   (N = 468) (N = 455)   (N = 229)
BL mean 146.2 145,0 146.1   147.1 145.0   146.0
Mean % Δ -15.6% -31.1% -36.3% -5.2%b -36.9% -36.7% 0.2%b -42.4%
a Trilipix + statin vs. Trilipix monotherapy
b Trilipix + statin vs. corresponding statin monotherapy
Low-dose statin = rosuvastatin 10 mg, simvastatin 20 mg, or atorvastatin 20 mg
Moderate-dose statin = rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg
High-dose statin = rosuvastatin 40 mg, simvastatin 80 mg, or atorvastatin 80 mg
BL = Baseline
% Δ = Percent change from baseline to final value

A total of 1895 patients who completed 12 weeks of treatment in the double-blind, controlled studies were treated in the 52-week, long-term extension study. Patients received Trilipix co-administered with the moderate-dose of the statin that had been used in the double-blind, controlled study in which they were enrolled. Whether combination therapy was initiated during the double-blind, controlled studies or introduced during the long-term extension study, the treatment effect of combination therapy was observed within four weeks, and was sustained over the duration of treatment in the long-term study. A total of 568 patients completed 52 weeks of treatment with Trilipix co-administered with statins. Mean 52-week values and mean percent change from baseline (at time of enrollment in randomized controlled trials) were 91.7 mg/dL (38.2%) for LDL-C, 47.3 mg/dL (+24.0%) for HDL-C, 135.5 mg/dL (-47.6%) for TG, 117.9 mg/dL (-45.7%) for non-HDL-C, 26.2 mg/dL (-53.1%) for VLDL-C, 165.2 mg/dL (-35.4%) for Total-C, and 81.4 mg/dL (43.6%) for Apo B.

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 7).

Table 7: 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 8).

Table 8. 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: 9/14/2012
This monograph has been modified to include the generic and brand name in many instances.

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