The effect of fluvastatin on the pharmacokinetics and pharmacodynamics of ezetimibe.
OBJECTIVE
The objective of this study was to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and fluvastatin in healthy hypercholesterolemic subjects at clinically-relevant doses and to evaluate the potential for a pharmacokinetic drug interaction between ezetimibe and fluvastatin.


METHODS
In a single-center, evaluator-blind, placebo-controlled, multiple-dose, parallel-group study 32 healthy subjects with hypercholesterolemia were randomized to 4 treatments administered once daily for 14 days: ezetimibe 10 mg plus ezetimibe placebo, fluvastatin 20 mg plus ezetimibe placebo, fluvastatin 20 mg plus ezetimibe 10 mg, and ezetimibe placebo. Blood samples were collected to measure serum lipids and to determine steady-state pharmacokinetics.


RESULTS
Ezetimibe 10 mg significantly (p < or = 0.01) decreased total-cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations compared to placebo at Day 14. Fluvastatin 20 mg also caused a significant (p = 0.01) reduction in total-cholesterol and a decrease in LDL-C at Day 14 compared to placebo, however, the decrease in LDL-C did not reach statistical significance (p = 0.08). The coadministration of ezetimibe 10 mg and fluvastatin 20 mg caused significantly (p < or = 0.01) greater mean percent reductions in LDL-C and total-cholesterol than fluvastatin 20 mg alone or placebo at Day 14. Fluvastatin had no clinically significant effect on the pharmacokinetics of ezetimibe. On average, ezetimibe appeared to decrease the rate and extent of fluvastatin bioavailability.


CONCLUSIONS
Coadministration of ezetimibe and fluvastatin was safe and well tolerated and caused significant incremental reductions in LDL-C and total cholesterol compared to fluvastatin administered alone. The pharmacokinetics of ezetimibe were not affected by coadministration with fluvastatin. The apparent decrease in fluvastatin exposure on administration with ezetimibe was likely to be due to the parallel study design and two pharmacokinetic outliers and is considered of no clinical significance.
Reyderman
Larisa
L
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA. larisa.reyderman@spcorp.com
Kosoglou
Teddy
T
Cutler
David L
DL
Maxwell
Stephen
S
Statkevich
Paul
P
D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001384:Azetidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged
D000924:Anticholesteremic Agents; D001384:Azetidines; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D000069438:Ezetimibe