伊布利特在中国健康受试者中的群体药代动力学和药效学研究

发布时间：2019-04-27 21:03

【摘要】：目的建立伊布利特在健康受试者中的群体药代动力学和药效学模型,研究伊布利特在人体的剂量-暴露量-药物效应关系及变异。方法按单中心、随机、剂量递增试验设计,共纳入40名健康受试者。研究分2个阶段,阶段1按公斤体重进行给药,将20名受试者随机分为3组:5μg·kg~(-1)组(n=4),10μg·kg~(-1)组(n=10)和20μg·kg~(-1)组(n=6);阶段2按固定剂量给药,将20名受试者随机分为3组:0.5 mg组(n=6),0.75 mg组(n=6)和1.0 mg组(n=8)。2个阶段的给药方式均为10 min内匀速静脉注射相应剂量的伊布利特。每名受试者采集13个伊布利特血药浓度数据和29个QT间期数据,用NONMEM 7.2建立和评价群体药代动力学和药效学模型。结果伊布利特药代动力学模型符合线性消除的三室模型,药效学模型符合Sigmoid E_(max)模型,群体药效学参数Sigmoid方程指数(γ)和QT间期最大效应(E_(max))的个体间变异为133.50%和64.10%。结论伊布利特在健康受试中的群体药代动力学和药效学模型稳定、可靠。伊布利特的药效在人群中存在明显的个体间差异,对伊布利特使敏感的患者在使用伊布利特是应及时地进行剂量的调整,以在转复的同时尽量避免药物不良反应的发生。
[Abstract]:Aim to establish a population pharmacokinetic and pharmacodynamic model of ibutilide in healthy volunteers, and to study the dose-exposure-drug effect relationship and variation of ibutilide in healthy volunteers. Methods according to the design of single center, random, dose increasing trial, 40 healthy subjects were enrolled. 20 subjects were randomly divided into 3 groups: 5 渭 g kg~ (- 1) group (n = 4), 10 渭 g kg~ (- 1) group (n = 10) and 20 渭 g kg~ (- 1) group (n = 6). In stage 2, 20 subjects were randomly divided into three groups: 0.5 mg group (n = 6). In 0.75 mg group (n = 6) and 1.0 mg group (n = 8), the corresponding dose of ibutilide was intravenously injected intravenously in 10 min. The population pharmacokinetic and pharmacodynamic models were established and evaluated by using NONMEM 7.2 to establish and evaluate the population pharmacokinetic and pharmacodynamic models, which were collected from 13 plasma concentrations of ibutilide and 29 QT interval data from each participant. Results the pharmacokinetic model of Ibutilide was in agreement with the three compartment model of linear elimination, and the pharmacodynamics model was consistent with the Sigmoid E _ (max) model. The Sigmoid equation index (纬) and the maximum effect of QT interval of population pharmacodynamics parameters were 133.50% and 64.10% of the population pharmacodynamics parameters, respectively. The interindividual variations of E_ (max) were 133.50% and 64.10%, respectively. Conclusion the population pharmacokinetic and pharmacodynamic models of ibutilide in healthy subjects are stable and reliable. There is a significant individual difference in the efficacy of ibulide in the population. It is necessary to adjust the dosage of ibutilide in order to avoid the occurrence of adverse drug reactions as far as possible in order to avoid the occurrence of adverse drug reactions in the use of ibutilide in patients who are sensitized to ibutilide in order to avoid the occurrence of adverse drug reactions.
【作者单位】：北京协和医学院中国医学科学院阜外医院卫生部心血管药物临床研究重点实验室;
【基金】：科学技术部国家科技重大专项基金资助项目(2012ZX09303008-001)
【分类号】：R969.1

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