Lipidil Micro - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Lipidil Micro - Scientific Information

Manufacture: Abbott
Country: Canada
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: Capsules
Ingredients: Fenofibrate, lactose, pregelatinized starch, magnesium stearate, sodium laurylsulfate, reticulated polyvinyl-pyrrolidone.

Pharmaceutical Information

Drug Substance

Proper name: fenofibrate
Chemical name: 2-(4-(4-chlorobenzoyl) phenoxy)-2-methyl-propanoic acid 1-methylethyl ester.
Structural formula:
Molecular formula: C20 H21 O4 Cl
Molecular weight: 360.83
Description: Fenofibrate is a crystalline, cream-colored, odourless and tasteless powder.
Melting point: 79 to 82°C.
Solubilities: Fenofibrate is practically insoluble in water, soluble in ethanol, freely soluble in acetone and chloroform.

Dosage Forms, Composition and Packaging

LIPIDIL MICRO (fenofibrate, micronized formulation) capsules are formulated for oral administration containing micronized fenofibrate and are available in 200 mg.

LIPIDIL MICRO 200 mg capsules are supplied as orange, hard gelatin capsules. The capsules are available in boxes of 30 capsules.

Listing of Non-Medicinal Ingredients

Each LIPIDIL MICRO 200 mg capsule contains 200 mg fenofibrate with the following non-medicinal ingredients: lactose, magnesium stearate, pregelatinized starch, reticulated polyvinyl-pyrrolidone, sodium laurylsulfate.

Utilizing an original and specific process of manufacturing, the size of the particles of fenofibrate contained in LIPIDIL MICRO is reduced, thus providing an increase in the effective surface area of particles to facilitate the dissolution rate and absorption.

Stability and Storage Recommendations

Keep at room temperature (15 to 25°C). Avoid excessive humidity.

Pharmacology

Animal Pharmacology

The antilipidemic activity of fenofibrate was investigated in normal and hyperlipidemic rats. Fenofibrate significantly lowers total lipids, LDL and VLDL-cholesterol, and triglyceride levels. At the same time it has been found to variably increase HDL-cholesterol concentrations. Its effect is more pronounced in hyperlipidemic rats and those fed high fat diets than in normal rats and those fed standard diets. Studies comparing fenofibrate with clofibrate have found that fenofibrate is a potent cholesterol-lowering drug.

The pronounced hypolipidemic effect in hyperlipidemic animals suggests that fenofibrate reduces cholesterol by enhancing the rate of cholesterol elimination. In normocholesterolemic rats, the main effect of fenofibrate is an inhibition of cholesterol biosynthesis.

Fenofibrate has no anti-inflammatory, cardiovascular, respiratory, CNS, autonomic nervous system, or other basal metabolism activities.

Pharmacokinetics and Clinical Pharmacology

Pharmacokinetics

In rats, dogs and man, fenofibrate is poorly absorbed from the gastrointestinal tract. This absorption is increased when the compound is administered in oil with food.

In man, a dose of 300 mg per day of non-micronized fenofibrate produced mean steady-state plasma drug concentrations ranging between 10 and 15 mcg/ml after 5 days of administration.

Fenofibrate is metabolized by hydrolysis to its active form, fenofibric acid. In man, fenofibric acid is eliminated conjugated with glucuronic acid. In rats this glucuroconjugation is very low and in dogs, practically non-existent. In these two species the main metabolic pathway is carbonyl reduction. The excretion in rats is principally a biliary excretion. In man, within 7 days after oral administration of fenofibrate with food, about 60 % is excreted in the urine and 25 % in the feces.

The elimination half-life of fenofibric acid is about 7-8 hours in rats and 24 hours in dogs. In man, the elimination half-life of fenofibric acid is about 20-24 hours. This value is not modified after multiple dosing. Very minor changes of pharmacokinetic parameters were observed in elderly subjects, but in patients with severe renal failure, significant accumulation was observed with a large increase of the half-life.

No sex related differences in pharmacokinetics and metabolism were observed in any species.

Fenofibric acid is extensively bound (> 99 %) to plasma proteins. This binding is not saturable.

Four specific pharmacokinetic studies were performed with LIPIDIL MICRO, (fenofibrate, micronized formulation) capsules 200 mg and one with LIPIDIL MICRO, capsules 67 mg.

A first single dose study in 18 healthy volunteers (9 M, 9 F) demonstrated that one capsule of LIPIDIL MICRO 200 mg was bioequivalent to one capsule containing 300 mg of non-micronized fenofibrate. In this balanced crossover study, the two formulations were administered immediately after a high-fat meal. The mean results are presented in the following table:

 AUC
(mg.l-1.h)
Cmax
(mg.l-1)
tmax
(h)
t2
(h)
LIPIDIL MICRO
(200 mg capsule)
176.711.05.915.4
LIPANTHYL 300 mg
non-micronized fenofibrate
171.310.75.617.9
95 % confidence interval
(Westlake)
  14.1 %  15 %  

A second single dose study in 18 healthy male volunteers demonstrated that one LIPIDIL MICRO 200 mg capsule is bioequivalent to three LIPIDIL 100 mg capsules (non-micronized fenofibrate) taken simultaneously.

The two formulations were administered immediately after a high-fat meal according to a balanced crossover design. The mean results are presented in the following table :

 AUC
(mg.l-1.h)
Cmax
(mg.l-1)
tmax
(h)
t2
(h)
LIPIDIL MICRO
(200 mg capsule)
178.28.9622.9
3 x LIPIDIL
(100 mg capsules)
180.010.2622.0
95 % confidence interval
(Westlake)
12.9 %31.4 %-12.4 %

In a third cross-over study, 18 healthy volunteers (8 F, 10 M) received either one LIPIDIL MICRO 200 mg capsule or three LIPIDIL 100 mg capsules once daily, during a low fat, low calorie meal, for 10 days.

The comparison of the pharmacokinetic parameters obtained at steady-state (Day 10) with the two formulations shows that the amount of fenofibrate absorbed is slightly higher with one LIPIDIL MICRO capsule 200 mg than with three 100 mg capsules of non-micronized fenofibrate (LIPIDIL) but also that the better absorption of LIPIDIL MICRO leads to a better homogeneity of the fenofibric acid plasma concentrations. This lower inter-subject variability with LIPIDIL MICRO is shown by the decrease of the coefficients of variation of AUC0-24, Cmax as well as Cmin obtained on Day 10. The mean values obtained on Day 10 and their coefficients of variation (CV %) are presented in the following table:

 AUC0-24
(mg.l-1.h)
Cmax
(mg.l-1)
Cmin
(mg.l-1)
tmax
(h)
t2
(h)
LIPIDIL MICRO
(200 mg capsule)
154.1
(19 %)
10.8
(23 %)
3.9
(24 %)
4.6
(20 %)
26.1
(50 %)
3 x LIPIDIL
(100 mg capsules)
119.4
(45 %)
8.6
(46 %)
3.2
(54 %)
5.6
(34 %)
23.5
(40 %)

In a fourth cross-over study, 5 healthy adult volunteers (male) received either one LIPIDIL MICRO 200 mg capsule or three LIPIDIL 100 mg capsules once daily, during a standard supper containing 40% lipids, for 10 days.

The comparison of the pharmacokinetic parameters obtained at steady-state (Day 10) with the two formulations shows that the amount of fenofibrate absorbed is slightly higher with three capsules of non-micronized fenofibrate (LIPIDIL) than with LIPIDIL MICRO capsules 200 mg. The mean values of pharmacokinetic parameters measured at Day 10 (CV %) are presented in the following table:

 AUC0-24
(mg.l-1.h)
Cmax
(mg.l-1)
tmax
(h)
t2
(h)
LIPIDIL MICRO
(200 mg capsule)
335.5
(34 %)
20.1
(25 %)
9.2
(4 %)
15.1
(59 %)
3 x LIPIDIL
(100 mg capsules)
409.0
(31 %)
25.5
(23 %)
7.0
(36 %)
15.3
(34 %)

The apparent discrepancy of the results of the two multiple-dose studies can be explained by the difference in fat content of the meals used in these studies and by the difference of particle size of fenofibrate in the two formulations.

The larger sized particles of fenofibrate contained in the non-micronized formulation (LIPIDIL) are indeed poorly absorbed in the presence of a low-fat meal whereas the smaller particles of LIPIDIL MICRO are already well absorbed.

Fenofibrate dissolves more easily in the presence of a larger amount of fat and food, this seems to affect the absorption of non-micronized fenofibrate more than that of micronized fenofibrate.

One specific pharmacokinetic study was performed with LIPIDIL MICRO, capsules 67 mg: 24 healthy male volunteers took part and completed this two-way, open randomized, cross-over study. Each volunteer received a single oral dose of each formulation with a standard breakfast and with a one week interval between doses.

Values obtained for the two formulations were as follows:

 Cmax
(mg.l-1)
tmax
(h)
AUC
(mg.l-1)
t 1/2
(h)
MRT
(h)
LIPIDIL MICRO
(capsules 67 mg)
Mean
sd


3.7
0.5


4.0*
(2.0-7.0)


62.1
19.0


19.7
6.1


25.2
6.0
LIPIDIL
(capsules 100 mg)
Mean
sd


4.0
0.9


4.0*
(2.0-6.0)


59.6
21.8


19.0
5.8


26.5
6.3

* : Median (range)

sd: Standard deviation

In summary, under the conditions of the studies, the data show that biological equivalence was achieved between LIPIDIL MICRO and LIPIDIL.

Clinical Pharmacology

Action on Lipid Parameters

The oral administration of 300 mg/day of fenofibrate for one week significantly reduced the plasma cholesterol and triglyceride levels in normolipidemic subjects. However, no change in HDL cholesterol levels was observed.

The effects of fenofibrate 300 mg/day, clofibrate 1500 mg/day and placebo on plasma lipoprotein and biliary lipid composition were compared in a double-blind study involving 12 normolipidemic subjects. Each treatment lasted two weeks. Fenofibrate lowered plasma cholesterol by 17 %, triglycerides by 9 % and LDL cholesterol by 16 %.

Fenofibrate 400 mg/day was administered for one month to 18 patients with hyperlipoproteinemia who failed to achieve normal lipid levels with a lipid-lowering diet. Fenofibrate treatment significantly reduced the total plasma cholesterol concentrations by 14 %, plasma triglycerides by 49 % and VLDL triglycerides by 62 %. No significant change was observed in HDL cholesterol concentration. LDL-cholesterol was reduced in patients with Type IIa and IIb hyperlipoproteinemia and increased in Types IV and V.

Lipoprotein-lipase activity was significantly increased.

In a double-blind study, two parallel groups of hyperlipidemic patients were treated with either 400 mg/day of fenofibrate (15 patients) or placebo (8 patients) for one month.

Significant decreases in total cholesterol, triglycerides and Apo-B were observed in the fenofibrate treated group, along with a significant increase in HDL-cholesterol.

Uricosuric Action

Fenofibrate decreased the plasma uric acid levels in normal as well as hyperuricemic subjects. In a study involving 10 normal male volunteers, single doses of 300 mg of fenofibrate were compared to benzbromarone. A uricosuric action was observed with both drugs. During a 14 day study in hyperlipidemic patients, a 28 % decrease in plasma uric acid concentration was observed less than four days after the onset of treatment with 300 mg/day of fenofibrate. This effect remained constant until the end of the study. An additional study conducted in healthy volunteers confirmed the rapid onset of the fenofibrate-induced hypouricemic effect and demonstrated the increased capability of the kidneys under these conditions to eliminate uric acid without damage to the proximal tubules.

Effect on Lithogenic Index

By virtue of structural similarity to other fibrates, fenofibrate might be suspected to increase the risk of gallstones as a result of increased cholesterol excretion via the bile.

Thus, five investigators have studied the biliary lithogenic index in fenofibrate-treated patients. In most studies, the lithogenic index was shown to be increased but the effect of fenofibrate was not marked and the degree of significance varied from one study to another. The relative proportions of bile lipids were also affected by fenofibrate treatment.

It is not known how fenofibrate treatment modifies the lipid composition of the bile.

Human Liver Biopsies

Two specific studies have been conducted in hyperlipidemic patients to evaluate the potential hepatocellular toxicity of fenofibrate. Examination of biopsies from liver samples of 38 patients including 28 receiving LIPIDIL over a mean period of approximately 2 years did not show any difference between treated and untreated patients. Peroxisomes were relatively rare, and macroscopic light and electron-microscopic observations revealed no sign of treatment-associated cellular abnormality. A similar study, taking biopsies from 10 patients who had, on average, received LIPIDIL for 9 months, and comparing these with tissue from 13 hyperlipidemic patients who had only received dietary treatment did not show any morphological difference between the two groups or any significant difference in the number or in the size of peroxisomes.

Clinical Experience

The activity of fenofibrate has been evaluated in more than 150 clinical trials performed in the U.S., Canada and Europe. The majority of these were conducted with non-micronized fenofibrate at a daily dose of 300 mg.

US Studies

Two multicenter, double-blind, placebo-controlled studies were conducted in the U.S., one in patients with Type II hyperlipoproteinemia, the other in Type IV/V patients.

Type II Study

Two hundred and twenty seven (227) hypercholesterolemic patients (181 Type IIa and 46 Type IIb) were enrolled during 6 months. After the double- blind phase, the study became open and all patients were given fenofibrate for the ensuing 6 month period.

One hundred and sixteen (116) patients received fenofibrate (100 mg t.i.d.) and one hundred and eleven (111) received placebo. At the end of this first period, ninety-eight (98) of the one hundred and sixteen (116) who were given fenofibrate and ninety-four (94) of the one hundred and eleven (111) patients who were given placebo, entered the second 6 month open phase of fenofibrate treatment.

Fenofibrate reduced the mean plasma concentrations of total cholesterol and VLDL-cholesterol in both Type IIa and IIb patients. LDL-cholesterol concentration was substantially decreased in all Type IIa patients, whereas there was little change in the Type IIb patients in whom the pre- treatment LDL-cholesterol levels were relatively normal. The mean concentrations of HDL-cholesterol were increased in both types of patients. Plasma triglyceride levels were decreased in the hypertriglyceridemic Type IIb patients. These effects were observed in the double-blind and open phases of the study (table 1).

Table 1: Effect of fenofibrate on percent change of lipoprotein lipids from baseline
Plasma Lipid
Parameter
Double-
Blind Phase
n = 92
Open Phase
n = 73
Double-
Blind Phase
n = 24
Open Phase
n = 21
Total cholesterol- 16 %- 18 %- 15 %- 24 %
LDL-cholesterol- 20 %- 22 %- 3 %- 20 %
VLDL-cholesterol- 34 %- 38 %- 53 %- 64 %
Total triglyceride- 34 %- 30 %- 41 %- 51 %
HDL-cholesterol+ 12 %+ 8 %+ 14 %+ 11 %
LDL/HDL-
cholesterol
- 27 %- 25 %- 14 %- 26 %

N.B. p-values<0.01 for differences between fenofibrate and placebo groups for all parameters except LDL-cholesterol in type IIB. Inversely, placebo treatment induced no statistically significant changes in the lipid parameters.

Type IV/V Study

One hundred forty seven (147) patients entered the study and all were stabilized on a low-fat diet. Following a placebo baseline period, patients were stratified according to plasma triglyceride (TG) levels (group A, 350-499 mg/dl, group B, 500-1.500 mg/dl) and randomly assigned to treatment with either 100 mg fenofibrate or one placebo capsule three times a day with meals. Demographically, the treatment groups were similar. A dramatic reduction in total TG levels occurred in the fenofibrate-treated patients but not in the placebo-treated patients. This effect, seen in both group A (46 %) and group B (55 %) patients, reached near maximum reduction in only 2 weeks of treatment, and continued throughout the 8 week treatment period. In both groups, fenofibrate treatment also decreased very low-density lipoprotein (VLDL) TG, total cholesterol and VLDL cholesterol, and increased high-density lipoprotein (HDL) levels (table 2).

LDL cholesterol levels increased 45 % from baseline in group B but not in group A. It should be noted that baseline LDL cholesterol levels were considerably depressed in group B as compared with group A patients.

Table 2: Percent change in lipid/lipoprotein values (mg/dl) from baseline to end-point
Group A Group B
Fenofibrate Placebo Fenofibrate Placebo
Total TG- 46 %- 1 %- 55 %+ 7 %
VLDL-TG- 44 %+ 3 %- 51 %+ 19 %
Cholesterol Total- 9 %+ 3 %- 14 %0 %
HDL+ 20 %+ 4 %+ 23 %+ 5 %
VLDL- 45 %+ 6 %- 49 %+ 11 %
LDL+ 15 %*+ 12 %+ 45 %- 4 %

Mean value rounded to nearest whole number.

* Not significantly different from placebo at p<0.05. All other changes with fenofibrate were significantly different from placebo at p ranging from 0.05 to <0.001

Canadian Study

Seventeen (17) patients with hypercholesterolemia were included in this six month open study. The dosage of fenofibrate was 100 mg t.i.d. Twelve (12) patients had familial hypercholesterolemia with tendon xanthomas (FHX) and five (5) patients were suffering from various types of hyperlipidemia including two cases of mixed familial hyperlipidemia, one case of Type IV hyperlipidemia and two cases of familial dysbetalipoproteinemia (Type III). Ten (10) patients showed serum cholesterol levels greater than 400 mg/dl; severe atherosclerosis was present in four other patients.

Plasma cholesterol and triglyceride concentrations were measured monthly and VLDL-C, LDL-C and HDL-C concentrations were measured every three months. These results were compared to the values obtained during a period of diet control. In the 12 patients suffering from familial hypercholesterolemia with tendon xanthomas, fenofibrate was very effective in lowering both cholesterol (mean decrease 19.8 percent) and LDL-C (mean decrease of 20.4 percent) (p < 0.0001 in both cases). However, the drug had no effect on HDL-C. Ten of the 12 patients showed a response characterized by a significant decrease in serum cholesterol of 15 percent or more. A marked and significant effect was observed in three of the other five patients. This effect, apparent on both cholesterol (decreases ranging from 33.6 to 38.2 percent) and triglycerides (decreases ranging from 36.3 to 77.8 percent), was accompanied by a corresponding effect on VLDL-C and a significant increase in HDL-C. One case of mixed familial hyperlipidemia proved resistant to treatment and the treatment in one Type III patient had to be interrupted after 3 months because of deterioration of lipoprotein profile and digestive problems.

In nine hundred and seventy one (971) patients with hyper-cholesterolemia (Type IIa), fenofibrate decreased the levels of total cholesterol (-16 to -30 %), LDL-cholesterol (-20 to -33 %) and apoprotein B (-14 to -37 %). HDL-cholesterol levels were variably affected depending on initial levels (-15 to +28 %). In eight hundred and fifty four (854) patients with mixed hyperlipidemia (Type IIb), more variable decreases were observed in total (-3 to -36 %) and LDL-cholesterol levels (-11 to -29 %), as well as substantial decreases in triglyceride levels (-19 to -67 %). In five hundred and seven (507) patients with hypertriglyceridemia (Type IV), marked decreases of triglycerides (-30 to -70 %) and VLDL-triglycerides (-47 to -70 %) were obtained following fenofibrate treatment. Results observed in short-term trials were maintained over long-term treatment periods.

European Studies

Non-micronized formulation (LIPIDIL)

Thirty-one (31) short-term studies of up to twelve (12) months duration, and six (6) long-term trials of up to six (6) years duration were conducted in Europe, involving two thousand four hundred and forty nine (2449) patients. In most studies, the recommended fenofibrate dose of 300 mg daily, administered in three equally divided doses, was used; occasionally, this dose was increased to 400 mg or 600 mg, or reduced to 200 mg daily depending on patient response.

Micronized formulation (LIPIDIL MICRO)

Specific clinical studies were performed with LIPIDIL MICRO.

The first clinical trial, a double blind comparative trial with LIPIDIL MICRO (one 200 mg capsule per day), LIPIDIL (100 mg three times daily) and matched placebo, of 3 months treatment duration, demonstrated comparable clinical response on all lipidic parameters with both the intent-to-treat and efficacy analysis.

The results of this study indicate that the fenofibrate treatments, 3 x 100 mg or 1 x 200 mg micronized, are significantly more active than the placebo on lipid parameters: cholesterol, triglycerides, LDL-cholesterol fraction and apolipoprotein B. The two treatments did not present any noticeable activity on the HDL-cholesterol or apolipoprotein A1 concentrations when they were subnormal at T0.

In the intent-to-treat analysis, the two treatments showed equivalent success levels of 73.4% for 3 x 100 mg fenofibrate and 71.9 % for 1 x 200 mg micronized fenofibrate and significantly greater than that observed in the placebo group (14.8 %).

In the analysis of efficacy, the two treatments decreased the mean cholesterol concentrations by more than 15 % versus the placebo group and this difference was significant (p < 0.0001).

Concerning triglycerides, the difference between the means for each of the fenofibrate groups and the placebo group is greater than the comparison value (30 % of placebo).

The second clinical trial conducted in Germany was established to evaluate the general acceptability associated with efficacy on lipid parameters of LIPIDIL MICRO. From patients evaluated for efficacy, there were 45.1% patients with type IIa and 69.6 % patients with type IIb classified as good responders on total cholesterol at T3. The total number of good responders for triglycerides (patients type IIb and IV) was 71.4% at T3 and 77.7% at T12. The treatment effect was consistent throughout the 12 months of the study.

After 3 months of treatment the mean value of total cholesterol was lowered in patients with type IIa from 311.4 mg/dl to 258.3 mg/dl with a mean decrease of 17 %. In patients with type IIb the mean value of total cholesterol lowered from 328.0 mg/dl to 266.5 mg/dl with a mean decrease of 18.6 %.

After 3 months of treatment the mean value of triglycerides was lowered in patients with type IIb from 254.8 mg/dl to 165.7 mg/dl with a mean decrease of 34.4 %. In patients with type IV the mean value of triglycerides was lowered from 383.8 mg/dl to 231.1 mg/dl with a mean decrease of 37.9 % after 3 months of treatment.

Toxicology

Acute Toxicity

Results from studies in mice, rats, hamsters and dogs indicate a low toxicity for fenofibrate with the highest administered doses (3200 to 24000 mg/kg), resulting in no deaths over the 7-day observation period. Autopsy findings were negative.

Chronic Toxicity Studies

Rats with normal or high cholesterol diet were treated for 7 days by gavage with fenofibrate at 0, 3, 10, 30, 100 and 300 mg/kg/day or clofibrate at 20, 60, 200 and 600 mg/kg/day. SGOT levels were raised in treated rats but SGPT levels remained within the normal range for rats on normal diet and were only slightly elevated in rats on the high cholesterol diet.

Dose-related hepatomegaly and proliferation of peroxisomes occurred, at doses above 30 mg/kg/day. In a second but similar study of drug metabolising enzymes, rats were treated daily by gavage for 7 days with fenofibrate at 0 or 100 mg/kg or clofibrate 200 mg/kg. The absence of significant change in the parameters measured suggests that the mechanisms resulting in hepatomegaly caused by both fibrates had little effect on cell organelles involved in drug metabolism and protein synthesis. In a third study in rats, oral doses of fenofibrate (0 to 1000 mg/kg) were given for 3 months. Depression of blood lipids was seen at all dose levels. SGOT and SGPT values were increased at 500 and 1000 mg/kg.

Hepatomegaly was a consistent finding at all dose-levels reaching a maximum of 78 % increase in weight compared to controls but appeared to regress rapidly. There were no other significant findings in the histological examination.

A 7-month study in dogs with 50 and 100 mg/kg/day and a 24-month study with 25 mg/kg/day were carried out. None of the dogs died but there was substantial weight loss associated with cholelithiasis and some interstitial nephritis. No important changes were observed in the biological parameters. Livers were apparently normal.

Fenofibrate (0, 12, 50 or 500 mg/kg) or clofibrate (200 mg/kg) was administered via a banana preparation, during 12 months to Rhesus monkeys. No fenofibrate-related effect with regard to toxicity was noted in any of the test groups during the study. No evidence of compound- related histomorphologic alterations was present in the animals sacrificed. The Rhesus monkey resembles man where biopsy studies show no signs of peroxisome proliferation during up to 2 years of fenofibrate treatment.

Carcinogenicity Studies

Five rodent feeding studies have shown that target organs for tumorigenic effects of fenofibrate are liver, pancreas and testis.

Mice showed increased liver weight with intrahepatic cholestasis and some degenerative changes but not liver tumors with 50 mg/kg/day for 22 months.

Dose-related increases in liver and kidney weight were seen in mice treated with 10 to 200 mg/kg/day of fenofibrate for 80 weeks.

Gross hepatomegaly associated with cholestasis was seen at the high dose level and in clofibrate (200 mg/kg/day) treated mice with occasional cholangitis and periportal fibrosis. Neoplastic lesions were confined to the liver with significant increases in hepatocellular carcinoma at the high dose of fenofibrate in both sexes. Hepatocellular adenomas were also increased in males. In clofibrate-treated mice there was an excess of hepatic adenomas in females but not in males.

Both fenofibrate and clofibrate were found to be associated with an increased incidence of hepatocellular hypertrophy, lobular dysplasia and Kupffer cell pigmentation in another long-term toxicity study (93 weeks) on mice. In both sexes the incidence of total hepatic neoplasms and carcinomas was significantly increased by the high dose of fenofibrate (200 mg/kg). At the intermediate dose (60 mg/kg) the combined tumor incidence was almost significant in males but not in females, while incidence of carcinomas was not significantly increased in males and absent in females. Also, clofibrate (400 mg/kg) significantly increased the total tumor incidence but not carcinomas in males; females were unaffected.

Rats which received fenofibrate (0, 10, 45 or 200 mg/kg/day) or clofibrate (200 mg/kg/day) mixed with their diet for a 2-year period showed no significant differences in mortality over the study period. Significant increases in incidences of hepatocellular carcinoma were found in the high dose fenofibrate group of animals of both sexes, in mid dose fenofibrate males, and in clofibrate treated males. Mid-dose fenofibrate males and clofibrate-treated males and females also showed significantly increased incidence of hepatocellular adenomas. Well differentiated pancreatic acinar cell carcinomas and adenomas were increased in a dose- related manner in the fenofibrate treated males, and higher incidences were also evident in the clofibrate males.

The chronic toxicity and carcinogenicity of fenofibrate was further studied in rats (0, 10 and 60 mg/kg/day) in order to compare treatment- related responses with those produced by clofibrate (400 mg/kg/day) and gemfibrozil (250 mg/kg/day) during 117 weeks of treatments. The absolute and relative weights of the liver were increased in all treatment groups except with 10 mg/kg fenofibrate. Although comparatively low, an incidence of hepatocellular carcinoma was observed in gemfibrozil- treated rats, and neoplastic nodules were also found in the livers of 50 % of the males which survived up to the termination of the study. Fewer neoplastic nodules were seen in the clofibrate-treated rats but these animals had a high incidence of hepatocellular carcinoma at termination. A significantly increased incidence of pancreatic acinar cell adenoma was seen in the 60 mg/kg fenofibrate males, while this increase in females was not significant. A significant increase in acinar adenoma and a slight increase in acinar carcinoma occurred with clofibrate (400 mg/kg) and some adenomas were seen in gemfibrozil-treated rats. There was some excess of benign interstitial cell tumors of the testis in all treatment groups except the group that received 10 mg/kg of fenofibrate.

Reproduction and Teratology Studies

There was no evidence of any increase in malformation frequency in mice, rabbits and rats after administration of fenofibrate compared to that seen in controls. Examination of offspring from fenofibrate-treated dams and those having received clofibrate did not disclose any significant abnormalities when compared to offspring from the controls. 

With the highest dose levels at which the mothers were adversely affected, there was evidence of embryotoxicity in rats and rabbits.

Genetic Toxicity Studies

Gene mutations : In vitro tests for mutagenicity with either fenofibrate or fenofibric acid in the presence or absence of activating rat or human microsomal enzyme preparations, have all given negative results. Thus, fenofibric acid was without effect on gene mutation frequency in bacteria (Ames), yeast and mouse lymphoma cells in culture.

In a second mouse lymphoma cell comparative study, there was no response to clofibric acid while some increased response to fenofibric acid at the highest concentration used was discounted due to poor relative growth. Similar activity was seen with gemfibrozil at toxic concentrations in the absence of metabolic activation. In conclusion, all three fibrates were found to be non-mutagenic on the protocol criteria, both in the absence and presence of metabolic activation.

Chromosome aberrations : Some trace of an increased but not significant incidence of aberrations was seen in an in vitro mouse lymphoma cell multiple end point assay.

Chromosome abberrations as such were not seen in a more recent comparative in vitro study with CHO cells when testing clofibric acid and gemfibrozil as well as fenofibric acid.

However, clofibric acid did have a marginal effect in increasing sister chromatid exchange frequency.

The absence of excision repair in human originated HeLa cells incubated with a wide range of concentrations of fenofibric acid with or without S9, reaffirmed the essentially non-genotoxic nature of the product.

Direct effects on DNA : The ability to bind covalently to target organ DNA is a property common to chemical substances which act by direct initiation of the carcinogenic process at the nuclear level. This type of genotoxic activity can be studied in vivo by DNA assay in rodents treated with the radiolabelled drug.

Although binding of fenofibric and clofibric acids to proteins was readily observed, no binding to DNA was demonstrated after oral administration of C14-labelled fenofibric or clofibric acid. The data therefore exclude somatic mutations as responsible for the known hepatocarcinogenic activity of these fibrates in rodents.

In a second in vivo test the effects of fenofibric acid were compared with those of clofibric acid and gemfibrozil on DNA synthesis in mouse testicular tissue, as measured by the incorporation of 3H-thymidine. Any response is representative of changes in DNA synthesis in any testicular cells such as germ, Sertoli, Leydig or interstitial cells undergoing scheduled or unscheduled synthesis.

Both fenofibric acid and gemfibrozil caused modest increases in thymidine incorporation above control values. Clofibrate caused some inhibition of the incorporation of thymidine into DNA at the two lowest doses with a small increase at the highest. No positive control substance was used but it would be assumed that, for example, genotoxic alkylating agents might cause a decrease in incorporation due to an inhibition of DNA synthesis. Such inhibition or cell cycle delay is well known for such agents.

The increase in DNA synthesis as observed in mouse testicular tissue with fenofibric acid and gemfibrozil is difficult to evaluate in the absence of a positive control or historical data for this recently developed test, nevertheless such an effect might be anticipated of such agents which are known to cause peroxisome proliferation and which produce increased cell turnover. The occurrence of increased cell turnover would be in keeping with a non-genotoxic but promoting mode of such compounds in mice.

In a rat primary hepatocyte unscheduled DNA synthesis (UDS) assay in vitro, gemfibrozil, clofibric acid and fenofibric acid showed a negative response. None caused nuclear labelling significantly different from the control and no dose-related trends were evident.

Cell growth or malignant transformation in vitro : fenofibric acid was without effect on growth or malignant transformation of cultured mammalian cell lines.