Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil.
OBJECTIVE
Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between ezetimibe and gemfibrozil.


METHODS
This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of > or = 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of ezetimibe and gemfibrozil. The oral bioavailability of ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model.


RESULTS
Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC0-12 of gemfibrozil was 74.7 and 74.1 microg h/ml with and without ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (CI) = 92 - 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of ezetimibe and total ezetimibe (i.e. ezetimibe plus ezetimibe-glucuronide). Exposure to ezetimibe and total ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 - 173% for ezetimibe and 142 - 190% for total ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated.


CONCLUSIONS
The coadministration of ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA. larisa.reyderman@spcorp.com
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Reyderman
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Kosoglou
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Statkevich
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Pember
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Boutros
S E
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Maxwell
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Affrime
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Batra
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D000069438:Ezetimibe; D015248:Gemfibrozil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D000924:Anticholesteremic Agents; D001384:Azetidines; D000069438:Ezetimibe; D015248:Gemfibrozil