Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe.
OBJECTIVE
The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia.


METHODS
This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C > or = 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14.


METHODS
The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate.


RESULTS
Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (p < or = 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (p < or = 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (p < or = 0.05 vs placebo), and LDL-III (p < or = 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C(max) and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant.


CONCLUSIONS
Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.
Department of Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. teddy.kosoglou@spcorp.com
Teddy
T
Kosoglou
Paul
P
Statkevich
Jean-Charles
JC
Fruchart
Laura J C
LJ
Pember
Larisa
L
Reyderman
David L
DL
Cutler
Michel
M
Guillaume
Stephen E
SE
Maxwell
Enrico P
EP
Veltri
D000328:Adult; D001384:Azetidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D011345:Fenofibrate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016037:Single-Blind Method; D016896:Treatment Outcome
D001384:Azetidines; D000960:Hypolipidemic Agents; D000069438:Ezetimibe; D011345:Fenofibrate