氢溴酸伏硫西汀片在中国健康受试者中生物等效性研究

Bioequivalence of Vortioxetine Hydrobromide Tablets in Chinese Healthy Volunteers

目的:评价成都康弘药业集团股份有限公司生产的氢溴酸伏硫西汀片与参比制剂H.Lundbeck A/S公司生产的氢溴酸伏硫西汀片(心达悦■)在中国健康受试者中的生物等效性,为临床使用和一致性评价提供依据。方法:采用单中心、随机、开放、单次给药、两周期、两制剂、两交叉设计,将空腹给药和餐后给药的受试者均随机分成2组,每组受试者分别口服氢溴酸伏硫西汀片受试制剂和参比制剂10 mg,采血至服药240 h,采用HPLC-MS/MS法测定血浆中伏硫西汀的浓度。采用Phoenix WinNonlin(版本号:8.2)计算药动学参数,计算每个受试者的个体血药浓度,采用非房室模型(NCA)计算伏硫西汀的药动学参数,并对两种制剂进行生物等效性评价;在试验期间对受试者的临床观察指标进行相关的安全性评价。结果:受试者空腹口服受试制剂和参比制剂后,血浆伏硫西汀的主要药动学参数分别为:C_(max)(3.935±1.061)和(4.003±0.915)ng·min^(-1);AUC_(0-t)(308.23±107.51)和(305.74±115.16)ng·h·ml^(-1);AUC_(0-∞)(373.42±180.60)和(372.22±207.42)ng·h·ml^(-1)。受试者餐后口服受试制剂和参比制剂后,血浆伏硫西汀的主要药动学参数分别为:C_(max)(3.862±0.985)和(3.771±0.619)ng·ml^(-1);AUC_(0-t)(320.39±121.81)和(313.80±108.26)ng·h·ml^(-1);AUC_(0-∞)(394.04±200.91)和(379.18±170.80)ng·h·ml^(-1)。受试制剂与参比制剂的C_(max)、AUC_(0-t)、AUC_(0-∞)经对数转换后几何均值比的90%置信区间均在80.00%~125.00%范围内,符合生物等效性要求。本试验中无严重或重度(常见不良反应事件评价标准CTCAE≥3级)不良事件发生。结论:氢溴酸伏硫西汀片受试制剂与参比制剂具有生物等效性,在健康受试者中安全、耐受。

Objective:To evaluate the bioequivalence and safety of generic vortioxetine hydrobromide tablets(test)by comparing with the original brand tablets(reference)to provide evidence for clinical use and quality consistency evaluation.Methods:This study was a single-center,randomized,open-label,single-dose,two-period,two-sequence,and self-crossover design.Subjects participating in fasting trial or in fed trial were randomly divided into 2 groups receiving a single dose of test or reference vortioxetine hydrobromide tablets(10 mg).Blood samples were collected until 240 h after drug administration,and vortioxetine concentration in plasma was determined by HPLC-MS/MS.The pharmacokinetic parameters were calculated by using non-atrioventricular model with Phoenix WinNonlin 8.2 software to evaluate bioequivalence.The safety of clinical observation indexes of the subjects was evaluated during the trail.Results:The pharmacokinetic parameters of test and reference preparations in fasting state were as follows:C_(max) were(3.935±1.061)and(4.003±0.915)ng·min^(-1);AUC_(0-t) were(308.23±107.51)and(305.74±115.16)ng·h·ml^(-1);AUC_(0-∞)were(373.42±180.60)and(372.22±207.42)ng·h·ml^(-1).The pharmacokinetic parameters of test and reference preparations in fed state were as follows:C_(max) were(3.862±0.985)and(3.771±0.619)ng·ml^(-1);AUC_(0-t) were(320.39±121.81)and(313.80±108.26)ng·h·ml^(-1);AUC_(0-∞)were(394.04±200.91)and(379.18±170.80)ng·h·ml^(-1).The 90%confidence interval for the ratio of C_(max),AUC_(0-t) and AUC_(0-∞)under fasting and fed conditions were all within the bioequivalence acceptance range of 80.00%-125.00%.No serious adverse events or adverse events(CTCAE≥3 grade)occurred during the trial.Conclusion:The generic vortioxetine hydrobromide tablets are bioequivalent to the reference preparation.Both the preparations are well tolerated with good safety.