帕罗西汀片健康人体生物等效性研究及CYP2D6基因多态性对其药代动力学的影响

Bioequivalence of paroxetine tablet in healthy subjects and effect of CYP2D6 genetic polymorphisms on pharmacokinetics

目的研究帕罗西汀片仿制药和原研药在中国健康受试者中的生物等效性及安全性,并探讨CYP2D6基因多态性对帕罗西汀体内药代动力学(PK)参数的影响。方法按单中心、随机、开放、单次给药、两序列、两周期、双交叉设计,共入组26例中国健康成年受试者,在空腹条件下每周期分别单次口服帕罗西汀片的受试制剂或参比制剂20 mg。采用经确证的高效液相色谱-质谱联用法测定血浆帕罗西汀浓度,使用WinNonlin软件按非房室模型计算PK参数,并评价其生物等效性;同时测定受试者CYP2D6各单核苷酸多态性位点的基因型,并进行代谢表型活性评分,比较不同评分受试者PK参数的差异。结果受试制剂及参比制剂的主要PK参数如下:C_(max)分别为(5.28±3.71)和(5.74±4.70)ng·mL^(-1),Tmax分别为(5.12±1.63)和(4.69±1.52)h,AUC0-t分别为(109.02±101.29)和(113.26±111.32)ng·mL·h^(-1),AUC0-∞分别为(115.22±102.35)和(119.96±112.62)ng·mL·h^(-1),主要PK参数均值比的90%置信区间均在80.00%~125.00%范围内。试验期间所有不良事件均为轻度,药物不良反应发生率分别为11.54%和7.69%CYP2D6代谢表型活性评分较低的受试者C_(max)、AUC均显著高于评分较高者(P<0.05)。结论单次口服两种帕罗西汀片具有生物等效性;CYP2D6基因多态性对帕罗西汀体内PK参数具有显著影响。

Objective To investigate the bioequivalence and safety of generic and branded paroxetine tablet in Chinese healthy subjects and explorer the effect of CYP2D6 polymorphisms on the pharmacokinetic parameters.Methods An single-center,randomized,open-label,single-dose,two sequences,two periods,crossover method was employed.Twenty-six Chinese adult healthy subjects were enrolled and respectively administered single oral dose of 20 mg paroxetine tablet test and reference formulations in fasting condition.Plasma paroxetine concentration was determined by a confirmed LC-MS/MS assay.The pharmacokinetic parameters were calculated and bioequivalence was assessed using WinNonlin software with non-compartment model.The different CYP2D6 single nucleotide polymorphisms genotypes of the subjects were determined.Following calculating the phenotype activity score,the pharmacokinetics of paroxetine were compared in subjects with different scores.Results The main pharmacokinetic parameters of paroxetine tablet test and reference formulations are respectively as follows:C_(max) are(5.28±3.71)and(5.74±4.70)ng·mL^(-1);Tmax are(5.12±1.63)and(4.69±1.52)h;AUC0-tare(109.02±101.29)and(113.26±111.32)ng·h·mL^(-1);AUC0-∞are(115.22±102.35)and(119.96±112.62)ng·h·mL^(-1);the 90%confidential intervals of C_(max) and AUC for test formulation vs.reference formulation fall within the range of 80.00%~125.00%.The adverse events reported during the study were all mild,and the incidences of adverse reactions were respectively 11.54%and 7.69%.The Cm ax and AUC in the subjects with lower CYP2D6 phenotype activity scores are significantly higher than the others with higher scores(P<0.05).Conclusion The two formulations of paroxetine tablets are bioequivalent in oral single-dose.The pharmacokinetics of paroxetine are obviously affected by CYP2D6 polymorphisms.