Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil

Int J Clin Pharmacol Ther. 2004 Sep;42(9):512-8. doi: 10.5414/cpp42512.

Abstract

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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / pharmacokinetics*
  • Area Under Curve
  • Azetidines / administration & dosage
  • Azetidines / adverse effects
  • Azetidines / pharmacokinetics*
  • Cross-Over Studies
  • Drug Administration Schedule
  • Drug Interactions
  • Ezetimibe
  • Gemfibrozil / administration & dosage
  • Gemfibrozil / adverse effects
  • Gemfibrozil / pharmacokinetics*
  • Humans
  • Hyperlipidemias / drug therapy
  • Male
  • Middle Aged
  • Reference Values

Substances

  • Anticholesteremic Agents
  • Azetidines
  • Ezetimibe
  • Gemfibrozil