Pharmacokinetics and safety of ezetimibe/simvastatin combination tablet: an open-label, single-dose study in healthy Chinese subjects.

ABSTRACT

BACKGROUND AND OBJECTIVES: Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics. METHODS: This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10 mg and simvastatin 40 mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms. RESULTS: The pharmacokinetic parameters (mean ± SD) for total ezetimibe and free ezetimibe following a single dose were maximum plasma drug concentration (C(max)) 81.56 ± 26.62 and 9.40 ± 6.17 ng/mL; time to reach C(max) (t(max)) 0.93 ± 0.30 and 1.25 ± 1.27 h; elimination half-life (t(½)) 24.32 ± 13.27 and 18.90 ± 9.66 h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06 ± 241.45 and 126.01 ± 69.01 ng·h/mL, respectively. The pharmacokinetic parameters (mean ± SD) for simvastatin and simvastatin acid following a single dose were C(max) 11.92 ± 5.50 and 3.37 ± 1.78 ng/mL, t(max) 0.98 ± 0.28 and 3.73 ± 1.68 h, t(½) 4.19 ± 1.81 and 7.65 ± 7.96 h, and mean AUC(last) 33.63 ± 20.41 and 32.50 ± 18.79 ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study. CONCLUSION: Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.