| Title | Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects. | | Author(s) | Migoya EM, Bergman A, Hreniuk D, Matthews N, Yi B, Roadcap B, Valesky R, Liu L, Riffel K, Groff M, Zhao JJ, Musson DG, Gambale J, Kosoglou T, Statkevich P, Lasseter KC, Laurent A, Johnson-Levonas AO, Murphy G, Gottesdiener K, Paolini JF | | Institution | Merck Research Laboratories, Rahway, NJ 07065-0900, USA. elizabeth_migoya@merck.com | | Source | Int J Clin Pharmacol Ther 2006 Feb; 44(2):83-92. | | MeSH | Adolescent
Adult
Analysis of Variance
Anticholesteremic Agents
Area Under Curve
Azetidines
Cross-Over Studies
Drug Combinations
Drug Therapy, Combination
Female
Humans
Male
Middle Aged
Reference Values
Simvastatin
Tablets
Therapeutic Equivalency
Time Factors
Treatment Outcome
| | 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. | | Language | eng | | Pub Type(s) | Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
| | PubMed ID | 16502768 |
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