DEVELOPMENT AND PHARMACOLOGY OF FLUVASTATIN

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and h as been studied extensively in humans since 1986. It is structurally d istinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biophar maceutical properties relative to the other agents of this class. Abso rption of fluvastatin is virtually complete across all species, includ ing man, and is not affected by the presence of food. Systemic exposur e is limited, as fluvastatin is subject to first-pass metabolism, and the plasma half-life of the drug is approximately 30 minutes. Some 95% of a single dosage of fluvastatin is excreted via the biliary route, with less than 2% of this being the parent compound. Additionally, the re is no evidence of circulating active metabolites or accumulation du ring chronic dosing. Studies of the effect of food on the pharmacokine tics of fluvastatin have demonstrated marked reductions in the rate of bioavailability - from 40% to 60%; however, a comparison of fluvastat in administration with the evening meal or at bedtime has revealed no significant differences in the extent of bioavailability (area '' unde r the curve) of these two regimens. Furthermore, no significant differ ence in pharmacodynamic effect (reduction in low-density lipoprotein c holesterol levels) could be ascertained between mealtime dosing and be dtime dosing. The pharmacokinetics of fluvastatin have also been asses sed in various demographic groups. Relative to tee general population, plasma concentrations of fluvastatin do not vary as a function of eit her age or gender. In addition, administration to a patient population with hepatic insufficient resulted in a 2.5-fold increase in both the rate and extent of bioavailability relative to controls. Also, althou gh minimal alterations of fluvastatin clearance in patients with renal insufficiency are anticipated due to limited renal excretion (5%), a study in this patient group is currently underway to examine this furt her. Interaction studies have been performed with fluvastatin and seve ral drugs with which it might be coadministered. Cholestyramine, an an ionic-binding resin: has a considerable effect in lowering the rate an d extent of fluvastatin bioavailability. Although this effect was note d even when cholestyramine was given 4 hours prior to fluvastatin, thi s regimen did not result in diminished efficacy. Further, no effects o n either warfarin levels or prothrombin times were observed in a study involving concomitant administration of warfarin and fluvastatin. Mor eover, additional interaction studies with niacin and propranolol have not demonstrated any effect on fluvastatin plasma levels, and adminis tration to a patient population chronically receiving digoxin resulted in no difference in the extent of bioavailability of digoxin relative to control data. The results generated to date in clinical pharmacoki netic studies with fluvastatin thus support its use in a broad populat ion of hypercholesterolaemic patients.