Polymorphism in CYP2D6 affects the pharmacokinetics and dose escalation of paroxetine controlled- release tablet in healthy Chinese subjects
Polymorphism in CYP2D6 affects the pharmacokinetics and dose escalation of paroxetine controlled- release tablet in healthy Chinese subjects
复制标题
CYP2D6多态性影响帕罗西汀控释片在中国健康受试者中的药代动力学和剂量递增
DOI：
10.5414/cp203008
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发表时间：
2017-11-01
影响因子：
0.8
通讯作者：
Hu, Pei
中科院分区：
文献类型：
--
作者：
Chen, Rui;Shen, Kai;Hu, Pei
本研究在中国健康受试者中评价了CYP2D6多态性对控释帕罗西汀12.5 - 37.5 mg剂量范围内的药代动力学和剂量递增的影响。材料与方法：这是一项I期、开放标签、单次给药、三阶段交叉研究，其中12例健康受试者接受12.5、25和37.5 mg帕罗西汀控释片单次口服给药，两次给药之间有10天洗脱期。在研究药物给药后96小时内采集连续静脉血样，并采用LC-MS/MS进行分析。通过PCR和直接DNA测序检测CYP2D6基因型。采用WinNonlin软件进行非房室模型分析，计算帕罗西汀的药代动力学参数。使用线性混合效应模型评估帕罗西汀药代动力学的线性。结果如下：在12.5、25和37.5 mg帕罗西汀剂量下，快代谢型（EM）组中帕罗西汀的平均AUC（0-inf）暴露量分别比中代谢型（IM）组低10.3、3.6和3.2倍。EM或IM组在12.5 - 37.5 mg范围内均无明显的剂量比例关系。从12.5至25 mg帕罗西汀，EM组的C-max/剂量和AUC（0-inf）/剂量的平均比值分别为2.04和2.40，IM组分别为0.93和1.00。从12.5至37.5 mg帕罗西汀，EM组的C-max/剂量和AUC（0-inf）/剂量的平均比值分别为4.04和4.08，IM组分别为1.60和1.82。结论：控释帕罗西汀在12.5 - 37.5 mg剂量范围内单次给药后的药代动力学和剂量递增受CYP2D6多态性影响。与帕罗西汀剂量增加相关的药物暴露增加在CYP2D6 EM中比在IM中更明显。
This study evaluated the effects of CYP2D6 polymorphisms on the pharmacokinetics and dose escalation of controlled-release paroxetine over the dose range of 12.5 - 37.5 mg in healthy Chinese subjects. Materials and methods: This was a phase I, open-label, single-dose, three-period crossover study in which 12 healthy subjects received single oral doses of 12.5, 25, and 37.5 mg paroxetine controlled-release tablets with 10-day washout between doses. Serial venous blood samples were collected for 96 hours after study-drug administration and analyzed with LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Pharmacokinetic parameters of paroxetine were calculated using noncompartmental analysis with WinNonlin software. The linearity of paroxetine pharmacokinetics was assessed using a linear mixed-effect model. Results: The exposure for paroxetine with regard to mean AUC(0-inf) in the extensive metabolizer (EM) group was 10.3-, 3.6-, and 3.2- fold lower at the doses of 12.5, 25, and 37.5 mg paroxetine, respectively, than that in the intermediate metabolizer (IM) group. There was no apparent dose proportionality over the range of 12.5 - 37.5 mg in either the EM or IM groups. From 12.5 to 25 mg paroxetine, the mean ratios of C-max/dose and AUC(0-inf)/dose were 2.04 and 2.40 in the EM group and 0.93 and 1.00 in the IM group, respectively. From 12.5 to 37.5 mg paroxetine, the mean ratios of C-max/dose and AUC(0-inf)/dose were 4.04 and 4.08 in the EM group and 1.60 and 1.82 in the IM group, respectively. Conclusion: The pharmacokinetics and dose escalation of controlled-release paroxetine after a single administration over the dose range of 12.5 - 37.5 mg were affected by CYP2D6 polymorphisms. The increase of drug exposure associated with an increase in the paroxetine dose was more pronounced in the CYP2D6 EMs than in the IMs.