Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.
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.
Migoya
E M
EM
Merck Research Laboratories, Rahway, NJ 07065-0900, USA. elizabeth_migoya@merck.com
Bergman
A
A
Hreniuk
D
D
Matthews
N
N
Yi
B
B
Roadcap
B
B
Valesky
R
R
Liu
L
L
Riffel
K
K
Groff
M
M
Zhao
J J
JJ
Musson
D G
DG
Gambale
J
J
Kosoglou
T
T
Statkevich
P
P
Lasseter
K C
KC
Laurent
A
A
Johnson-Levonas
A O
AO
Murphy
G
G
Gottesdiener
K
K
Paolini
J F
JF
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
D000924:Anticholesteremic Agents; D001384:Azetidines; D004338:Drug Combinations; D013607:Tablets; D019821:Simvastatin; D000069438:Ezetimibe