Application of a physiologically based pharmacokinetic model for the evaluation of single-point plasma phenotyping method of CYP2D6
Application of a physiologically based pharmacokinetic model for the evaluation of single-point plasma phenotyping method of CYP2D6
复制标题
基于生理学的药代动力学模型在CYP2D6单点血浆表型分析方法评价中的应用
DOI：
10.1016/j.ejps.2016.07.001
复制
发表时间：
2016-09-20
影响因子：
4.6
通讯作者：
Hu, Pei
中科院分区：
文献类型：
--
作者：
Chen, Rui;Rostami-Hodjegan, Amin;Hu, Pei
目的：从单点血浆中测定代谢率是一种潜在的很好的CYP2D6表型方法，可以缩短所需的时间间隔，增加数据的可靠性。很难进行大样本量的临床试验来评估这种多血浆点的表型方法。建立基于生理基础的药代动力学(PBPK)模型，在虚拟中国人群基础上进行模拟，评价CYP2D6的单点血浆表型方法。方法：利用右美沙芬(DM)及其代谢物右美沙芬(DX)口服给药后的药代动力学数据建立模型。结果：广泛代谢物(EM)的模拟AUC和C-max分别为1.01和0.81，中间代谢物(IMS)为0.90和0.81，不良代谢物(PM)为1.12和0.84。EMS的模拟AUC和C-max与观测平均值的比值分别为1.12和0.89，IMS为0.66和0.62。所有的比率都在预先定义的0.5-2的标准之内。在1000名不同表型的中国虚拟受试者中，DM和DX的药代动力学模拟结果表明，AUC和单点血浆中DM和DX的代谢率(MRDM/DX)在1-30h之间具有统计学意义的相关性(均为p值
Purpose: Determining metabolic ratio from single-point plasma is potentially a good phenotyping method of CYP2D6 to reduce the required time interval and increase the reliability of data. It is difficult to conduct large sample size clinical trials to evaluate this phenotyping method for multiple plasma points. A physiologically based pharmacokinetic (PBPK) model can be developed to do simulations based on the large virtual Chinese population and evaluate single-point plasma phenotyping method of CYP2D6.Methods: Pharmacokinetic data of dextromethorphan (DM) and its metabolite dextrorphan (DX) after oral administration were used for model development. The SimCYP (R) model incorporating Chinese demographic, physiological, and enzyme data was used to simulate DM and DX pharmacokinetics in different phenotype groups.Results: The ratios of the simulated to the observed mean AUC and C-max of DM were 1.01 and 0.81 for extensive metabolizers (EMs), 0.90 and 0.81 for intermediate metabolizers (IMs), and 1.12 and 0.84 for poor metabolizers (PMs). The ratios of the simulated to the observed mean AUC and C-max of DX were 1.12 and 0.89 for EMs, 0.66 and 0.62 for IMs. All ratios were within the predefined criterion of 0.5-2. The simulations of DM and DX pharmacokinetic profiles in 1000 virtual Chinese subjects with reported frequencies of different phenotypes indicated that statistically significant correlations were found between metabolic ratio of DM to DX (MRDM/DX) from AUC and from single-point plasma from 1 to 30 h (all p-values