Pharmacokinetics of fluvastatin and specific drug interactions.
Fluvastatin sodium (Lescol) is the first synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor to be studied extensively in humans. Absorption of fluvastatin is complete and unaffected by the presence of food. Systemic exposure is limited because of extensive 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% of 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 reductions in the rate of bioavailability (Cmax) of 40% to 60%. A comparison of drug administration with the evening meal or at bedtime revealed 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 population, plasma fluvastatin concentrations do not vary as a function of either age or gender. Administration of a single 40-mg dose to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both AUC and Cmax. Drug interaction studies with fluvastatin and cholestyramine (CME) demonstrated a lower rate and extent of fluvastatin bioavailability; no impact on efficacy was demonstrated when CME was given 4 h before fluvastatin dosing in clinical trials. Interaction studies with niacin and propranolol demonstrated no effects on fluvastatin plasma levels, and fluvastatin administered to a patient population chronically receiving digoxin had no effect on the AUC of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
H T
HT
Sandoz Research Institute, East Hanover, New Jersey 07936.
Jokubaitis
L A
LA
Troendle
A J
AJ
Hwang
D S
DS
Robinson
W T
WT
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism / Q000502:physiology; D001682:Biological Availability; D002792:Cholestyramine Resin / Q000032:analysis / Q000493:pharmacokinetics*; D004032:Diet; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000097:blood; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000097:blood / Q000493:pharmacokinetics; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; D014280:Triglycerides; D002792:Cholestyramine Resin; D009525:Niacin; D000077340:Fluvastatin; D004077:Digoxin; D011433:Propranolol