Bezafibrate

Bezafibrate lowers elevated blood lipids (triglycerides and cholesterol). Elevated VLDL and LDL are reduced by treatment with bezafibrate, whilst HDL-levels are increased. The activity of triglyceride lipases (lipoprotein lipase and hepatic lipoprotein lipase) involved in the catabolism of triglyceride-rich lipoproteins is increased by bezafibrate. In the course of the intensified degradation of triglyceride-rich lipoproteins (chylomicrons, VLDL), precursors for the formation of HDL are formed which explains an increase in HDL. Furthermore, cholesterol biosynthesis is reduced by bezafibrate, which is accompanied by a stimulation of the LDL receptor-mediated lipoprotein catabolism.

Studies have shown bezafibrate to be effective in treating hyperlipidaemia in patients with diabetes mellitus. Some cases showed a beneficial reduction in fasting blood glucose.

Significant reductions in serum fibrinogen levels have been observed in hyperfibrinogenaemic patients treated with bezafibrate.

There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.

Absorption

Bezafibrate is rapidly and almost completely absorbed from the standard tablet formulation.

A peak plasma concentration of about 8mg/l is reached after 1-2 hours following a single 200 mg dose in healthy volunteers.

A peak plasma concentration of about 14mg/L is reached after 2 hours following ingestion of 2 × 200 mg standard tablets given as a single dose in healthy volunteers.

With bezafibrate 400 mg modified release tablets, a peak concentration of about 8 mg is reached after about 4 hours. The relative bioavailability of bezafibrate retard compared to the standard form is about 70%.

Distribution

The protein-binding of bezafibrate in serum is approximately 95%. The apparent volume of distribution is 17 litres.

Biotransformation

50% of the administered bezafibrate dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides.

Elimination

Elimination is rapid with excretion almost exclusively renal. 95% of the activity of ¹⁴C-labelled drug is recovered in the urine and 3% in the faeces within 48 hours. 50% of the applied dose is recovered in the urine as unchanged drug and 20% in the form of glucuronides.

The rate of renal clearance ranges from 3.4 to 6.0 l/h. The elimination half-life is in the order of 1-2 hours.

Pharmacokinetics in special populations

Pharmacokinetic investigations in older people suggest that elimination may be delayed in cases of impaired liver function. Liver disease (except fatty liver) is a contraindication for the use of bezafibrate.

In elderly patients, there is a physiological reduction of the renal function with age. Bezafibrate dosage should be adjusted based on the serum creatinine and creatinine clearance values as indicated in the above table.

The elimination of bezafibrate is reduced in patients with impaired renal function and dosage adjustments are necessary to prevent drug accumulation and toxic effects.

Not surprisingly there is a correlation between creatinine clearance and the elimination half-life of bezafibrate; with decreasing creatinine clearance the elimination half-life is increasing.

Because of its high protein binding, bezafibrate cannot be dialysed (cuprophane filter). The use of bezafibrate is contraindicated in dialysis patients.

The chronic administration of a high dose of bezafibrate to rats was associated with hepatic tumour formation in females. This dosage was in the order of 30 to 40 times the human dosage. No such effect was apparent at reduced intake levels approximating more closely to the lipid-lowering dosage in humans.