Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin.
OBJECTIVE
The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective.


METHODS
Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only.


RESULTS
In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone.


CONCLUSIONS
The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.
Kosoglou
Teddy
T
Schering-Plough Research Institute, Kenilworth, NJ, USA.teddy.kosoglou@pcrop.com
Meyer
Ingo
I
Veltri
Enrico P
EP
Statkevich
Paul
P
Yang
Bo
B
Zhu
Yali
Y
Mellars
Lillian
L
Maxwell
Stephen E
SE
Patrick
James E
JE
Cutler
David L
DL
Batra
Vijay K
VK
Affrime
Melton B
MB
D000284:Administration, Oral; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001384:Azetidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D015992:Body Mass Index; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D000069438:Ezetimibe; D006801:Humans; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D004338:Drug Combinations; D019821:Simvastatin; D000069438:Ezetimibe