Fluvastatin

Fluvastatin, a fully synthetic cholesterol-lowering agent, is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Fluvastatin exerts its main effect in the liver and is mainly a racemate of the two erythro enantiomers of which one exerts the pharmacological activity. 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 ultimate result of these mechanisms is a reduction in the plasma cholesterol concentration.

Fluvastatin reduces total-C, LDL-C, Apo B, and triglycerides, and increases HDL-C in patients with hypercholesterolaemia and mixed dyslipidaemia.

Absorption

Fluvastatin is absorbed rapidly and completely (98%) after oral administration of a solution to fasted volunteers. After oral administration of fluvastatin 80 mg prolonged-release tablets, and in comparison with the immediate-release capsules, the absorption rate of fluvastatin is almost 60% slower while the mean residence time of fluvastatin is increased by approximately 4 hours. In a fed state, the substance is absorbed at a reduced rate.

Distribution

Fluvastatin exerts its main effect in the liver, which is also the main organ for its metabolism. The absolute bioavailability assessed from systemic blood concentrations is 24%. The apparent volume of distribution (Vz/f) for the drug is 330 litres. More than 98% of the circulating drug is bound to plasma proteins, and this binding is not affected either by the concentration of fluvastatin, or by warfarin, salicylic acid or glyburide.

Biotransformation

Fluvastatin is mainly metabolised in the liver. The major components circulating in the blood are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. There are multiple, alternative cytochrome P450 (CYP450) pathways for fluvastatin biotransformation and thus fluvastatin metabolism is relatively insensitive to CYP450 inhibition.

Fluvastatin inhibited only the metabolism of compounds that are metabolised by CYP2C9. Despite the potential that therefore exists for competitive interaction between fluvastatin and compounds that are CYP2C9 substrates, such as diclofenac, phenytoin, tolbutamide, and warfarin, clinical data indicate that this interaction is unlikely.

Elimination

Following administration of 3H-fluvastatin to healthy volunteers, excretion of radioactivity is about 6% in the urine and 93% in the faeces, and fluvastatin accounts for less than 2% of the total radioactivity excreted. The plasma clearance (CL/f) for fluvastatin in man is calculated to be 1.8 ± 0.8 L/min. Steady-state plasma concentrations show no evidence of fluvastatin accumulation following administration of 80 mg daily. Following oral administration of 40 mg fluvastatin, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Characteristics in patients

Plasma concentrations of fluvastatin do not vary as a function of either age or gender in the general population. However, enhanced treatment response was observed in women and in elderly people.

Since fluvastatin is eliminated primarily via the biliary route and is subject to significant pre-systemic metabolism, the potential exists for drug accumulation in patients with hepatic insufficiency.

Children and adolescents with heterozygous familial hypercholesterolaemia

No pharmacokinetic data in children are available.

The conventional studies, including safety pharmacology, genotoxicity, repeated dose toxicity, carcinogenicity and toxicity on reproduction studies did not indicate other risks for the patient than those expected due to the pharmacological mechanism of action. A variety of changes were identified in toxicity studies that are common to HMG-CoA reductase inhibitors. Based on clinical observations, liver function tests are already recommended. Further toxicity seen in animals was either not relevant for human use or occurred at exposure levels sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Despite the theoretical considerations concerning the role of cholesterol in embryo development, animal studies did not suggest an embryotoxic and teratogenic potential of fluvastatin.