Lipidil Supra - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Lipidil Supra - 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: Tablets
Ingredients: Fenofibrate, colloidal silicon dioxide, crospovidone, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium stearyl fumerate and sodium lauryl sulfate, soybean lecithin, talc, titanium dioxide and xantham gum.

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 SUPRA (fenofibrate, microcoated formulation) 160 mg tablets are formulated for oral administration containing microcoated fenofibrate.

LIPIDIL SUPRA 160 mg tablets are supplied as white, oblong, film-coated tablet and are embossed with the Fournier logo on one side and 160 on the other. The tablets are available in blister packs of 30 tablets.

Listing of Non-Medicinal Ingredients

Each LIPIDIL SUPRA 160 mg tablet contains 160 mg of fenofibrate with the following non- medicinal ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium stearyl fumerate and sodium lauryl sulfate, soybean lecithin, talc, titanium dioxide and xantham gum.

Stability and Storage Recommendations

Store at 15 to 30oC. Protect from light and moisture.

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

Fenofibrate is metabolized by hydrolysis to its active form, fenofibric acid. In man, fenofibric acid is eliminated conjugated with glucuronic acid.

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.

Fenofibric acid is extensively bound (> 99 %) to plasma proteins. This binding is not saturable. In a two-way, randomized, crossover bioavailability study, 200 mg fenofibrate, micronized formulation, was compared to 160 mg fenofibrate, microcoated formulation, (LIPIDIL SUPRA) in 24 healthy male volunteers. Each volunteer received a single oral dose of each formulation with a standard breakfast and with a one week interval between doses.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA A SINGLE DOSE STUDY
(Blood levels measured as fenofibric acid)

Bioavailability
Parameters
fenofibrate,
microcoated
- Tablet 160 mg -
mean (CV%)
fenofibrate,
micronized
- Capsule 200 mg -
mean (CV%)
Ratio
of
Means
90% Confidence
Interval Limits (%)
Lower Upper
AUCT (mcg.h/mL) 138.7 (26) arith.
134.0 (27) geom
152.0 (24) arith.
147.8 (24) geom
0.91 arith.
0.91 geom
88
88
94 arith.
94 geom
AUC (mcg.h/mL) 141.5 (27) arith.
136.5 (28) geom
155.3 (25) arith.
150.8 (25) geom
0.91 arith.
0.91 geom
88
88
95 arith.
94 geom
CMAX (mcg/mL) 7.98 (13) arith.
7.92 (13) geom
8.9 (17) arith.
8.8 (17) geom
0.89   arith.
0.90   geom
85
86
94  arith.
95  geom
TMAX (h) 3.9 (24) arith. 4.4 (15) arith. 0.88 arith.    
t1/2 (h) 20.1 (21) arith. 19.4 (21) arith. 1.03 arith.    

These data show that biological equivalence was achieved between LIPIDIL SUPRA and fenofibrate, micronized formulation. During the bioavailability study, three subjects reported gastrointestinal irritation after the administration of LIPIDIL SUPRA; none were reported after fenofibrate, micronized formulation. The causality of these events in relation to LIPIDIL SUPRA has not been established.

Clinical Studies

The effects of fenofibrate on total mortality, and cardiovascular mortality and morbidity have not been established.

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 fenofibrate, micronized formulation, at a daily dose of 200 mg.

Specific clinical studies were performed with fenofibrate, micronized formulation.

The first clinical trial followed a double-blind, parallel group versus placebo design. One hundred and eighty-nine patients (Type IIa; 120 and Type IIb; 69) were randomized in three groups: placebo, 200 mg micronized fenofibrate and 3 x 100 mg non micronized fenofibrate. The ages of the patients ranged from 18 to 75 years. The intent-to-treat analysis indicated an efficacy level after 3 months (as assessed by the number of patients who experienced a cholesterol reduction > 15%) which was significantly greater in the micronized fenofibrate group (71.9%) than in the placebo group (14.8%). Micronized fenofibrate treatment was significantly more active than placebo in reducing total cholesterol (-18%), LDL-cholesterol (-22%), triglycerides (-19%) and apolipoprotein B (-24%).

The second clinical trial evaluated the effectiveness of micronized fenofibrate on lipid parameters. Of 131 eligible patients, 94 (31 Type IIa, 23 Type IIb and 40 Type IV) were evaluated for efficacy. Of those with Type IIa and Type IIb, 45.1% and 69.6%, respectively, were classified as good responders for total cholesterol. Of patients with Type IIb and IV, 71.4% and 77.7%, respectively, were considered good responders for triglycerides. 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 was lowered from 328.0 mg/dl to 266.5 mg/dl, with a mean decrease of 18.6 %. 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 %.

A placebo-controlled, double-blind study was also performed in 418 patients with type 2 diabetes: The Diabetes Atherosclerosis Intervention Study (DAIS). The patients were randomized to either fenofibrate 200 mg once daily or to placebo for an average of 38 months. The main objectives were to determine the safety of 200 mg fenofibrate, micronized formulation, in a population of type 2 diabetic patients and to measure angiographic responses by quantitative coronary angiography (QCA). Male (73%) and female patients were included in the study. They presented with adequate glycemic control, total cholesterol/high density lipoprotein cholesterol ratio ³ 4, and either low density lipoprotein cholesterol (LDL-C) from 3.5 to 4.5 mmol/l with triglycerides (TG) £ 5.2 mmol/l, or TG from 1.7 to 5.2 mmol/l with LDL-C £ 4.5 mmol/l. An adequate QCA with previous CABG or PTCA or at least one coronary segment with a minimal detectable stenosis was also required.

The primary efficacy parameter was the mean segment parameter, averaged per patient, to test a null hypothesis of no difference between fenofibrate- and placebo-treated patients. Additional secondary angiographic efficacy parameters were also analyzed.

The angiographic results showed that the primary endpoint (mean segment diameter per patient) did not reach statistical significance and the change from baseline was not clinically meaningful (see following table 4). The change in mean segment diameter was minimal in both groups over the treatment period, with no statistical difference between groups.

TABLE 4: DAIS study: Mean coronary angiogram values (± S.D.) averaged per patient and per segment at baseline and at the end of study (ITT population)
  Fenofibrate Placebo p-value
Per patient analysis N=207 N=211  
- Mean segment
diameter (mm)
     
Baseline 2.70 (0.45) 2.67 (0.45) 0.494
Final 2.62 (0.49) 2.56 (0.50) 0.173
- Minimum segment
diameter (mm)
     
Baseline 2.14 (0.44) 2.10 (0.44) 0.457
Final 2.05 (0.46) 1.98 (0.48) 0.028
- Percent diameter
stenosis (%)
     
Baseline 21.8 (7.8) 21.8 (7.4) 0.958
Final 24.1 (9.8) 25.7 (10.8) 0.02
  Fenofibrate Placebo p-value*
Per segment analysis N=1884 N=1993  
-Mean diameter (mm)      
Baseline 2.76 (0.84) 2.72 (0.83) 0.145
Final 2.68 (0.87) 2.62 (0.87) 0.037
-Minimum diameter (mm)      
Baseline 2.20 (0.82) 2.16 (0.81) 0.077
Final 2.11 (0.84) 2.03 (0.83) 0.541
% stenosis      
Baseline 21.0 (13.1) 21.4 (12.8) 0.309
Final 23.0 (15.9) 24.9 (17.2) 0.059

*p-values for Student’s t test and for covariance analysis to compare treatment groups, respectively, at baseline and at the end of the study (last available value on treatment). Statistical significance was established at 0.025.

The changes in lipid levels were also monitored in the type 2 diabetic patients included in the DAIS study. The major lipid values at baseline and at the end of the study are shown in the following table 5 for both the fenofibrate- and placebo-treated groups.

TABLE 5: DAIS study: Mean major lipid values (±S.D.) at baseline and at the end of the study (ITT population)
  Fenofibrate Placebo p-values*
-Total cholesterol
(mmol/L)
     
Baseline 5.56 (0.80) 5.58 (0.72) 0.751
Final 4.93 (0.83) 5.42 (0.79) < 0.001
- Total triglycerides
(mmol/L)
     
Baseline 2.56 (1.23) 2.52 (1.22) 0.706
Final 1.65 (0.90) 2.16 (1.20) < 0.001
- HDL-C (mmol/L)      
Baseline 1.00 (0.19) 1.04 (0.21) 0.045
End of study 1.06 (0.26) 1.06 (0.24) 0.045
-Calc. LDL-C (mmol/L)      
Baseline 3.36 (0.71) 3.39 (0.72) 0.532
Final 3.12 (0.69) 3.38 (0.73) 0.042
TC / HDL-C      
Baseline 5.63 (1.08) 5.51 (1.10) 0.115
Final 4.87 (1.27) 5.35 (1.25) < 0.001
Apo AI (g/L)      
Baseline 1.24 (0.18) 1.26 (0.277) 0.277
Final 1.33 (0.22) 1.29 (0.20) 0.02

*p-values for Student’s t test and for covariance analysis to compare treatment groups at baseline and at the end of the study (last available value on treatment)

Safety was closely monitored in the DAIS study for both adverse events and laboratory anomalies. Fenofibrate was used safely in type 2 diabetic patients, as the overall incidence and severity of adverse events were comparable for the two treatment groups. The table 6 below summarizes the incidence of adverse events, by body system, observed in the fenofibrate and placebo treatment groups.

TABLE 6: DAIS study: Incidence of adverse events (AEs) by system, experienced by type 2 diabetic patients during treatment with fenofibrate or placebo (ITT population)
Body System Fenofibrate
(N=207)
Placebo
(N=211)

Total # pts. with at
least 1 AE
AEs Patients AEs Patients
Total AEs:
1710
201 (97.1%) Total AEs:
1759
202 (95.7%)
Body as a whole 371 (21.7%) 136 (65.7%) 362 (20.6%) 146 (69.2%)
Cardiovascular 183 (10.7%) 84 (40.6%) 220 (12.5%) 96 (45.5%)
Digestive 196 (11.5%) 86 (41.6%) 194 (11.0%) 87 (41.2%)
Endocrine 11 (0.6%) 10 (4.8%) 19 (1.1%) 11 (5.2%)
Hemic/lymphatic 31 (1.8%) 19 (9.2%) 23 (1.3%) 15 (7.1%)
Metabolic/nutritional 50 (2.9%) 32 (15.5%) 70 (4.9%) 41 (19.4%)
Musculo-skeletal 155 (9,1%) 84 (40.6%) 180 (10.2%) 84 (39.8%)
CNS 103 (6.0%) 59 (28.5%) 98 (5.6%) 58 (27.5%)
Respiratory 301 (17.6%) 108 (52.2%) 279 (15.9%) 105 (49.8%)
Skin/appendage 107 (6.3%) 58 (28.0%) 107 (6.1%) 48 (22.8%)
Special senses 73 (4.3%) 44 (21.3%) 90 (5.1%) 50 (23.7%)
Urogenital 118 (6.9%) 55 (26.6%) 103 (5.9%) 46 (21.8%)
Other 11 (0.6%) 9 (4.4%) 14 (0.8%) 11 (5.2%)

Clinical Pharmacology

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, non- micronized formulation, 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, non-micronized formulation. 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 of increasing the risk of gallstones as a result of increased cholesterol excretion via the bile.

The biliary lithogenic index in fenofibrate-treated patients was evaluated. 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 fenofibrate, non-micronized formulation, 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 fenofibrate, non-micronized formulation, 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.

Toxicology

All toxicology studies were performed using fenofibrate, non-micronized formulation.

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. AST levels were raised in treated rats but ALT 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. AST and ALT 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/day) or clofibrate (200 mg/kg/day) was administered in the food of Rhesus monkeys for 12 months. 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 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.

When given at a dose of 200 mg/kg/day, both fenofibrate and clofibrate produced gross hepatomegaly associated with cholestasis and 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 aberrations 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 radiolabeled drug.

Although binding of fenofibric and clofibric acids to proteins was readily observed, no binding to DNA was demonstrated after oral administration of C14-labeled 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.