Bezafibrate

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Abstract
Bezafibrate1 is a lipid-lowering drug, chemically related to clofibrate. At its recommended dosage of 200mg 3 times daily, or alternatively 400mg once daily as a sustained-release preparation, it produces substantial reductions in plasma triglyceride and cholesterol concentrations in patients with hypertriglyceridaemia and hypercholesterolaemia, respectively. Preliminary investigations indicate that a single daily dose of 400mg in a sustained-release preparation is as effective as 200mg 3 times daily. In patients with any type of hyperlipoproteinaemia bezafibrate also increases the plasma HDL-cholesterol concentration. These effects are equivalent in patients with primary hyperlipoproteinaemia or hyperlipoproteinaemia secondary to diabetes or renal disease, although dosage adjustment is important in the latter group. During long term therapy (2 to 4 years) the influence of bezafibrate on the lipid profile is sustained. The lipid-lowering effects of bezafibrate are at least equivalent to those of clofibrate, fenofibrate, colestipol, probucol or sustained release etofibrate. In addition, the increase in HDL-cholesterol tends to be at least as great as with all alternative treatments studied. Bezafibrate is rapidly eliminated, and thus does not accumulate during prolonged administration in patients with normal renal function. Experimental studies have shown bezafibrate to have a complex range of effects on lipoproteins and on the enzymes and receptors involved in lipid metabolism. However, its exact mechanism of lipid-lowering action is unclear. Bezafibrate enhances anticoagulation in hyperlipoproteinaemic patients requiring anticoagulant therapy, and preliminary investigations indicate that it reduces the plasma fibrinogen concentration, especially in patients with hyperfibrinogenaemia. These properties of bezafibrate could contribute to an antiatherogenic effect of the drug, but further investigation is required to establish the drug’s potential as chronic therapy in patients with hyperfibrinogenaemic atherosclerosis. Adverse reactions to bezafibrate have largely been restricted to gastrointestinal disturbances, with some cutaneous reactions and central nervous system effects. The incidence of side effects has been no greater than with comparative lipid-lowering drugs. In patients with renal disease, a few cases of marked elevation of serum creatine phosphokinase and myoglobin, and associated muscle cramps, have been reported (diagnosed as rhabdomyolysis). Hepatic enzyme induction by bezafibrate in rats results in hepatomegaly, but there has been no case of significant hepatotoxicity in man. Thus, bezafibrate is an effective and relatively well tolerated alternative to clofibrate and other lipid-lowering drugs in patients with primary hyperlipoproteinaemia types IIa, IIb or IV and some forms of secondary hyperlipoproteinaemia. However, the effect of bezafibrate on mortality from cardiovascular disease remains to be reported. Bezafibrate is a lipid-regulating agent. It effectively reduces plasma total cholesterol and triglyceride concentrations in normal and hyperlipidaemic animals, healthy human volunteers and patients with hyperlipoproteinaemia. An accompanying increase in high density lipoprotein (HDL) cholesterol, greater than or equal to that with either clofibrate or fenofibrate in man, results in an increase in the HDL: very low density lipoprotein (VLDL) + low density lipoprotein (LDL) cholesterol ratio. In hyperlipoproteinaemic patients the reduction in triglycerides is associated with a marked reduction in VLDL and a concurrent reduction in apolipoprotein B, the major protein constituent of VLDL. The mechanism by which bezafibrate reduces the plasma triglyceride concentration is believed to be via increased catabolism of VLDL by lipoprotein lipase, and to a lesser extent hepatic lipase. However, it is unclear whether this enzyme activation is a direct effect or subsequent to drug-induced changes in the protein constituents of lipoproteins. For example, bezafibrate has been reported to increase the concentration of apolipoprotein CII which activates lipoprotein lipase, but not apolipoprotein CIII which inhibits this enzyme. In animal studies bezafibrate inhibits the activity of 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, the enzyme controlling the rate-limiting step in the synthesis of cholesterol, and acyl-CoA cholesterol acyl transferase (ACAT) which converts intracellular free cholesterol to cholesterol ester. Such changes have not been confirmed in man. However, bezafibrate has been shown to increase the activity of LDL receptors in patients with type II hyperlipoproteinaemia, and since LDL receptor activity is dependent on the intracellular concentration of cholesterol this effect could result from inhibition of HMG CoA reductase. An increase in LDL receptor activity could account for the reduction in LDL-cholesterol observed in patients with type II hyperlipoproteinaemia. In type IV hyperlipoproteinaemic patients some authors have reported abnormalities in the size and cholesterol content of LDL. The abnormal lipoprotein binding properties and cellular handling of LDL which results is reverted to normal by bezafibrate therapy. The small increase in LDL-cholesterol seen in type IV hyperlipoproteinaemic patients could simply reflect a greater catabolism of VLDL in these patients than in type II patients. With regard to the influence of bezafibrate on HDL-cholesterol, increases in both apolipoprotein AI and AII have been reported, and it is unclear whether the increase in HDL is predominantly as HDL2 or HDL3. The activity of the enzyme lecithin: cholesterol acyltransferase (LCAT), which esterifies free cholesterol taken up by HDL, was inhibited by bezafibrate in one study in hyperlipoproteinaemic patients, but the results of other clinical and preclinical studies do not confirm this. Bezafibrate induces hepatomegaly in rats. This effect results from hepatic enzyme induction, with increased activity of both peroxisomal and some mitochondrial enzymes. Hepatic alkaline phosphatase and lactate dehydrogenase activities are also increased during bezafibrate administration in rats, although serum alkaline phosphatase concentrations are reduced consistently in animals and man. Hepatomegaly does not appear to develop following bezafibrate administration in most other animal species or in man. Moreover, even in rats it is not associated with any increased carcinogenic risk during prolonged drug administration. Incorporation of cholesterol into bile acids is one route for its excretion. An increase in the concentration of cholesterol in bile, or an increase in the lithogenic index, can increase the risk of gallstone formation. Small increases in the lithogenic index have been reported with bezafibrate in the short term, but do not seem to be maintained during prolonged administration. In patients with hyperlipidaemia bezafibrate inhibits platelet aggregation and enhances the effect of anticoagulants. In addition, it reduces the plasma fibrinogen concentration and plasma viscosity, and has been reported to enhance fibrinolytic activity. A preliminary, controlled study indicated that bezafibrate may be of clinical benefit in patients with hyperfibrinogenaemic atherosclerosis. Bezafibrate is rapidly and almost completely absorbed from the standard tablet formulation. A peak plasma concentration of about 10 mg/L is reached after about 2 hours following a single 300mg dose in healthy volunteers. The drug is 95% protein bound and has an apparent volume of distribution of about 17L. Elimination is rapid, with almost exclusive renal excretion. After a 300mg dose 94% of the drug was recovered in the urine within 24 hours (over 40% as unchanged drug) and the rate of renal clearance was 3.4 to 4.3 L/h. The elimination half-life of bezafibrate is about 2 hours. Compared with clofibrate, bezafibrate is more rapidly absorbed and has a lower peak plasma concentration and area under the plasma concentration-time curve (AUC) at steady-state. The elimination of bezafibrate is reduced in patients with renal insufficiency and dosage adjustments are necessary to prevent drug accumulation and toxic effects. There is a correlation between creatinine clearance and the elimination half-life of bezafibrate. Clinical trials with bezafibrate have concentrated on patients with the most commonly diagnosed types of hyperlipoproteinaemia, types Ha, IIb or IV. A few patients with types III or V hyperlipoproteinaemia have also been treated, but too few to permit fair assessment of the drug’s therapeutic value in such patients. In all patients, bezafibrate, normally at a dosage of 150 or 200mg twice or 3 times daily, reduces plasma total cholesterol and triglyceride concentrations. The reduction in triglyceride, which reaches a peak within the first 2 months of treatment, is about 40 to 50% in type IV patients, less in type IIb patients, and least (about 20 to 30%) in type IIa patients. There are corresponding, substantial reductions in VLDL triglyceride concentrations. Reductions in total cholesterol tend to be smaller (10 to 30%), especially in type IV patients. In fact, bezafibrate-induced changes in the concentration of the main plasma cholesterol reservoir, LDL-cholesterol, are dependent on pretreatment concentrations of this lipoprotein fraction, with an increase reported in patients with a pretreatment concentration below about 1.6 g/L. Thus, in type IV patients bezafibrate increases the LDL concentration by about 10%. The HDL-cholesterol concentration is increased by bezafibrate in all types of hyperlipoproteinaemia. This increase has been reported at between 10 and 30% in most studies, but is a delayed effect in comparison with changes in VLDL and total triglycerides, and may not be apparent within the first 6 weeks of treatment. Bezafibrate appears to have a greater effect on HDL-cholesterol concentration the lower the initial concentration. In short term studies an increase of over 50% has been reported in patients with a pretreatment concentration below about 0.3 g/L. Thus, bezafibrate may prove to be of therapeutic value in patients with HDL deficiency, although controlled, long term studies are necessary to confirm this. The lipid and lipoprotein changes induced by bezafibrate are maintained during prolonged administration (up to 4.5 years in 1 study). After treatment discontinuation the plasma cholesterol concentration returns to its pretreatment level relatively quickly while reduced plasma triglyceride and elevated HDL-cholesterol concentrations tend to be sustained for some time. An important limitation of the clinical data on bezafibrate is the absence of any published reports on the drug’s effect on mortality from cardiovascular disease in the long term. In comparative studies bezafibrate 150 or 200mg 3 times daily reduced plasma triglyceride and cholesterol concentrations to an extent equivalent to the changes induced by fenofibrate 300 to 400mg daily, similar or greater than those induced by clofibrate 1.5 to 2g daily, and greater than those induced by sustained release etofibrate 500mg daily in patients with type II or IV hyperlipoproteinaemia. Plasma triglyceride concentration was reduced to a greater extent by bezafibrate 600mg daily than by colestipol 20g daily or probucol lg daily. The increase in HDL-cholesterol after bezafibrate therapy tended to be similar or greater than that observed after any comparative treatment. The influence of bezafibrate on lipid and lipoprotein concentrations in diabetic patients with hyperlipoproteinaemia is comparable with that in non-diabetic patients. Bezafibrate also produces small reductions in the plasma glucose concentration in such patients, improving the control of diabetes; hypoglycaemia has not been reported and no adjustment of the dosage of antidiabetic medication has been required in clinical trials. In patients with impaired renal function who develop hypertriglyceridaemia, bezafibrate is an effective lipid-lowering drug, but a reduced dosage (depending on the pretreatment creatinine clearance rate) must be employed to avoid drug accumulation and toxic effects. Gastrointestinal disturbances are the most frequently reported adverse reactions to bezafibrate therapy, but as with most other symptoms (including cutaneous reactions, headache, dizziness, insomnia and loss of libido) they tend to be mild, occur within the first few months of therapy and resolve without the need for drug withdrawal. In comparative studies clinically significant side effects occurred equally rarely on bezafibrate as on clofibrate or fenofibrate. The incidence of drug withdrawal for side effects considered to be related to bezafibrate therapy was about 5% in a study of 3 months’ duration involving over 3500 patients. The serum alkaline phosphatase concentration is consistently reduced by about 10 to 30% during bezafibrate therapy, and this is accompanied by a reduction in γ-glutamyl transferase, and a small reduction in alanine aminotransferase during prolonged therapy. It is doubtful whether these changes are of clinical significance. However, statistically significant increases in mean serum creatinine and creatine phosphokinase have also been reported in clinical studies. These mean changes have been small, but marked elevation of creatine phosphokinase has been reported in individual patients, accompanied by muscle cramps in some and with a diagnosis of drug-induced rhabdomyolysis in others; such patients have all had reduced renal function and, despite dosage adjustment, were considered to have received an excessive dosage of bezafibrate. In addition, in a few patients with chronic renal failure bezafibrate accelerated the decline of renal function, but again the patients were found to have excessively high plasma concentrations of bezafibrate. Small reductions in haemoglobin, white blood cell count and plasma viscosity, and some interaction with the fibrinolytic system have been reported during bezafibrate therapy. The clinical significance of such effects is unclear at present. The recommended dosage of bezafibrate in patients with hyperlipoproteinaemia and normal renal function is 200mg 3 times daily. As with all other pharmacological intervention in patients with lipid abnormalities, bezafibrate should not be introduced until non-pharmacological intervention has proved inadequate. Recent evidence indicates that bezafibrate may be as effective when administered once daily at a dose of 400mg (as conventional tablets or a sustained release formulation) as 3 times daily, but further controlled studies are necessary to confirm this. Similarly, further studies are required to establish the efficacy and tolerability of bezafibrate 5 to 10 mg/kg twice daily in children with familial hypercholesterolaemia. In patients with impaired renal function drug accumulation can be minimised by using a dosage of 400mg daily in those with a creatinine clearance of 40 to 60 ml/min, 200mg daily or every second day if the creatinine clearance is 15 to 40 ml/min, and 200mg every third day in renal dialysis patients. Care should be taken to monitor for signs of further renal function deterioration and skeletal muscle damage in these patients. When bezafibrate is administered to patients receiving anticoagulation with coumarins, it is necessary to reduce the dosage of anticoagulant by about 30%.
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