PHARMACOKINETICS OF FLUVASTATIN AND SPECIFIC DRUG-INTERACTIONS

Fluvastatin sodium (Lescol) is the first synthetic 3-hydroxy-3-methylg lutaryl-coenzyme A (HMG-CoA)-reductase inhibitor to be studied extensi vely in humans. Absorption of fluvastatin is complete and unaffected b y the presence of food. Systemic exposure is limited because of extens ive sequestration by the liver and/or first-pass metabolism, a plasma half-life of approximately 30 min, no circulating active metabolites, and no accumulation of drug during chronic dosing. Approximately 95% o f a single dose of fluvastatin is excreted via the biliary route with less than 2% as the parent compound. Studies investigating the effect of food on fluvastatin pharmacokinetics have demonstrated marked reduc tions in the rate of bioavailability (C(max)) of 40% to 60%. A compari son of drug administration with the evening meal or at bedtime reveale d no significant differences in either the extent of bioavailability ( area under the curve; AUC) or pharmacodynamic effect [reduction in low -density lipoprotein cholesterol (LDL-C)]. Relative to the general pop ulation, plasma fluvastatin concentrations do not vary as a function o f either age or gender. Administration of a single 40-mg dose to a pat ient population with hepatic insufficiency resulted in a 2.5-fold incr ease in both AUC and C(max). Drug interaction studies with fluvastatin and cholestyramine (CME) demonstrated a lower rate and extent of fluv astatin bioavailability; no impact on efficacy was demonstrated when C ME was given 4 h before fluvastatin dosing in clinical trials. Interac tion studies with niacin and propranolol demonstrated no effects on fl uvastatin plasma levels, and fluvastatin administered to a patient pop ulation chronically receiving digoxin had no effect on the AUC of digo xin compared with controls. Thus far, data from clinical pharmacokinet ic studies with fluvastatin support its use in a broad population of h ypercholesterolemic patients.