Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects

Int J Clin Pharmacol Ther. 2006 Feb;44(2):83-92. doi: 10.5414/cpp44083.

Abstract

Objective: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA).

Methods: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25).

Results: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated.

Conclusions: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Analysis of Variance
  • 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 Combinations
  • Drug Therapy, Combination
  • Ezetimibe
  • Female
  • Humans
  • Male
  • Middle Aged
  • Reference Values
  • Simvastatin / administration & dosage
  • Simvastatin / adverse effects
  • Simvastatin / pharmacokinetics*
  • Tablets
  • Therapeutic Equivalency
  • Time Factors
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Azetidines
  • Drug Combinations
  • Tablets
  • Simvastatin
  • Ezetimibe