title: Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.
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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065-0900, USA. elizabeth_migoya@merck.com
authors.forename: E M
authors.initials: EM
authors.lastname: Migoya
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.forename: D
authors.initials: D
authors.lastname: Hreniuk
authors.forename: N
authors.initials: N
authors.lastname: Matthews
authors.forename: B
authors.initials: B
authors.lastname: Yi
authors.forename: B
authors.initials: B
authors.lastname: Roadcap
authors.forename: R
authors.initials: R
authors.lastname: Valesky
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Riffel
authors.forename: M
authors.initials: M
authors.lastname: Groff
authors.forename: J J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: D G
authors.initials: DG
authors.lastname: Musson
authors.forename: J
authors.initials: J
authors.lastname: Gambale
authors.forename: T
authors.initials: T
authors.lastname: Kosoglou
authors.forename: P
authors.initials: P
authors.lastname: Statkevich
authors.forename: K C
authors.initials: KC
authors.lastname: Lasseter
authors.forename: A
authors.initials: A
authors.lastname: Laurent
authors.forename: A O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.forename: K
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: J F
authors.initials: JF
authors.lastname: Paolini
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; 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; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D004338:Drug Combinations; D013607:Tablets; D019821:Simvastatin; D000069438:Ezetimibe