A variety of clinical studies have demonstrated that elevated levels of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein B (a membrane transport complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level of HDL-C.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium) reduced Total-C, LDL-C, apolipoprotein B, and triglycerides while producing an increase in HDL-C. Increases in HDL-C are greater in patients with low HDL-C (< 35 mg/dL). Neither agent had a consistent effect on either Lp(a) or fibrinogen. The effect of Lescol or Lescol XL induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular mortality has not been determined.

Mechanism of Action

Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.

Pharmacokinetics/Metabolism

Oral Absorption

Fluvastatin is absorbed rapidly and completely following oral administration of the capsule, with peak concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces the rate but not the extent of absorption. At steady state, administration of fluvastatin with the evening meal results in a two-fold decrease in Cmax and more than two-fold increase in tmax as compared to administration 4 hours after the evening meal. No significant differences in extent of absorption or in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in higher than expected plasma fluvastatin concentrations.

Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form. In vivo studies showed that stereo-selective hepatic binding of the active form occurs during the first pass resulting in a difference in the peak levels of the two enantiomers, with the active to inactive peak concentration ratio being about 0.7. The approximate ratio of the active to inactive approaches unity after the peak is seen and thereafter the two enantiomers decline with the same half-life. After an intravenous administration, bypassing the first-pass, metabolism, the ratios of the enantiomers in plasma were similar throughout the concentration-time profiles.

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