| Indication |
To be used as an adjunct to dietary therapy to prevent
cardiovascular events. May be used as secondary prevention in patients
with coronary heart disease (CHD) to reduce the risk of requiring
coronary revascularization procedures, for reducing progression of
coronary atherosclerosis in hypercholesterolemic patients with CHD, and
for the treatment of primary hypercholesterolemia and mixed
dyslidipidemia. |
| Pharmacodynamics |
Fluvastatin, the first synthetically-derived HMG-CoA reductase
inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower
cholesterol and triglyceride levels associated with primary
hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and
IIb), to slow the progression of coronary atherosclerosis in patients
with CHD and as secondary prevention therapy in patients with CHD to
reduce the risk of requiring coronary revascularization procedures.
Although similar to lovastatin, simvastatin, and pravastatin,
fluvastatin has a shorter half-life, no active metabolites, extensive
protein binding, and minimal CSF penetration. Fluvastatin acts primarily
in the liver. It is prepared as a racemate of two erythro enantiomers
of which the 3R,5S enantiomer exerts the pharmacologic effect. |
| Mechanism of action |
Fluvastatin selectively and competitively inhibits the hepatic
enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA
reductase is responsible for converting HMG-CoA to mevalonate, the
rate-limiting step in cholesterol biosynthesis. Inhibition results in a
decrease in hepatic cholesterol levels which stimulates the synthesis of
LDL receptors and increases hepatic uptake of LDL cholesterol. The end
result is decreased levels of plasma total and LDL cholesterol. |
| Absorption |
Rapidly and almost completely absorbed (> 90%), but undergoes
extensive first pass metabolism. Bioavailability is 24% (range 9-50%). |
| Volume of distribution |
|
| Protein binding |
98% bound to plasma proteins |
| Metabolism |
Undergoes hepatic metabolism primarily via hydroxylation of the
indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and
6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl
fluvastatin and beta-oxidation of the side chain also occurs.
Metabolized primarily by the CYP2C9 isozyme system (75%), and to a
lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated
metabolites retain some pharmcological activity, but are present as
conjugates (glucuronides and sulfates) in the blood and are rapidly
eliminated via bile into feces. |
| Route of elimination |
Fluvastatin is metabolized in the liver, primarily via
hydroxylation of the indole ring at the 5- and 6-positions. In vitro
studies demonstrated that fluvastatin undergoes oxidative metabolism,
predominantly via 2C9 isozyme systems (75%). No significant (<6%)
renal excretion of fluvastatin occurs in humans. |
| Half life |
1-3 hours |
| Clearance |
- 0.8 L/h/kg
- 107 +/- 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg]
- 87.8 +/- 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily]
- 108 +/- 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single]
- 64.2 +/- 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily]
|
| Toxicity |
Generally well-tolerated. May cause GI upset (diarrhea, nausea,
constipation, gas, abdominal pain), myotoxicity (mypothy, myositis,
rhabdomyolysis), and hepatotoxicity. |
