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/MetabolismOral 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.

Fluvastatin administered as Lescol XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the Lescol immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6H) and increased the bioavailability of the XL tablet by approximately 50%. Once Lescol XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high-fat meal is much less than the peak concentration following a single dose or twice daily dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is large (42%-64% CV for Cmax and AUC), and especially so after a high-fat meal (63%-89% for Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after Lescol XL administration.

Distribution 

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.

Metabolism

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolized in a similar manner.

In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%). (See PRECAUTIONS: Drug Interactions Section).

Elimination

Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of fluvastatin; however, there was a 2.3- fold accumulation of total radioactivity.

Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of the immediate- release capsule. Following once daily administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal half-life of Lescol XL was about 9 hours as a result of the slow-release formulation. 

Single-dose and steady-state pharmacokinetic parameters in 33 subjects with hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release tablets are summarized below: 

Special PopulationsRenal Insufficiency:

No significant (<6%) renal excretion of fluvastatin occurs in humans.

Hepatic Insufficiency:

Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is eliminated primarily via the biliary route. Therefore, the potential exists for drug accumulation in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS). 

Fluvastatin AUC and Cmax values increased by about 2.5- fold in hepatic insufficiency patients. This result was attributed to the decreased presystemic metabolism due to hepatic dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency patients were comparable to those observed in healthy subjects.

Age:

Plasma levels of fluvastatin are not affected by age. 

Gender:

Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations than men for the immediate- release capsule. This is most likely due to body weight differences, as adjusting for body weight decreases the magnitude of the differences seen. For Lescol XL, there are 67% and 77% increases in systemic availability for women over men under fasted and high- fat meal conditions.

Pediatric:

Pharmacokinetic data in the pediatric population are not available.