Bioequivalence And Pharmacokinetics Studies Of Zopiclone Tablets In Chinese Healthy Volunteers

ObjectiveEstablished and verified a UPLC-MS/MS analytical method that can be applied to quantitative determination of zopiclone in plasma.Applied the method to studies on bioequivalence and pharmacokinetics of zopiclone tablets in Chinese healthy volunteers,and clarified food effect on the pharmacokinetics of zopiclone.Methods1.A single-center,randomized,open-label,single dose,oral administration,three-cycle bioequivalence clinical trial was conducted to evaluate bioequivalence of test(7.5mg/tablet)and reference formulations(Sanofi Pharmaceuticals,Imovane(?),7.5mg/tablet)in healthy subjects on fasting status,with a wash period of 3 days during every cycle.2.Food effect studies on bioequivalence and pharmacokinetics were conducted to evaluate the bioequivalence of test and reference formulations in healthy subjects,and evaluate food effect on pharmacokinetic process of zolpiclone in healthy volunteers.Results1.The UPLC-MS/MS analysis method established in this research is simple,fast,sensitive and can completely separate zopiclone in 2minutes,with good linearity in the range of 2ng/mL?200ng/mL(within the plasma)(r2?0.99).All the methodological verification items in this study have obtained good results that met the acceptance criteria.The analytical methods developed in this study could be applied to the analysis of plasma biological samples in clinical trials.The results of fasting bioequivalence pharmacokinetic test in 9 healthy subjects were as follows:for zopiclone T1 and R formulations,the 90%confidence interval of Cmax was 91.07%?113.52%,the 90%confidence interval of AUC0-t was 93.11%?103.61%,the 90%confidence interval of AUC0-? was 93.19%?105.19%.For zopiclone T2 and R formulation,the 90%confidence interval of Cmax was 99.58%?122.61%,the 90%confidence interval of AUC0-t was 101.99%?113.37%,and the 90%confidence interval of AUC0-? was 101.37%?112.29%.All meeted the NMPA evaluation criteria for bioequivalence tests,so reference and test formulations in this study are considered to be bioequivalent.2.The results of food effect bioequivalence test in 20 healthy subjects were as follows:For fasting group,the 90%confidence interval of Cmax was 86.99%?119.39%,the 90%confidence interval of AUC0-t was 92.58%-103.88%,and the 90%confidence interval of AUC0-? was 92.64%?103.85%;For diet group,the 90%confidence interval of Cmax was 88.60%?119.46%,the 90%confidence interval of AUC0-t was 95.17%?102.49%,and the 90%confidence interval of AUC0-? was 95.47%?102.77%.Summary:This study established and validated a UPLC-MS/MS method that can be used for quantitative detecting zopiclone in human plasma,and was successfully used in zopiclone bioequivalence study.At the same time,the method was innovatively applied to food effect studies on bioequivalence and pharmacoknetic.