Differences in Cytochrome P450-Mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically Based Pharmacokinetic Modelling
Differences in Cytochrome P450-Mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically Based Pharmacokinetic Modelling
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DOI：
10.1007/s40262-013-0089-y
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发表时间：
2013-12-01
影响因子：
4.5
通讯作者：
Rowland-Yeo, Karen
中科院分区：
文献类型：
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作者：
Barter, Zoe E.;Tucker, Geoffrey T.;Rowland-Yeo, Karen
人用药品注册技术要求国际协调会议（ICH）指南强调，需要更好地了解种族对药物反应的影响，以尽量减少临床研究的重复，我们开发了一个中文数据库，用于预测主要由细胞色素P450（CYP）代谢的药物的群体动力学差异。相对于高加索人。这些预测应有助于告知在两个种族群体中重复体内药代动力学研究的必要性和这些研究的设计，中国人的人口统计学和生理学数据，沿着中国人中相关基因多态性的丰度和频率的信息，从文献来源中整理并纳入Simcyp基于人群的模拟器（A（R））（v11.1）。使用虚拟高加索人群和主要由特定CYP代谢的模型化合物的默认Simcyp参数值作为参考点。参与其代谢的药物和主要CYP是非那西丁（CYP 1A 2）、地昔帕明（CYP 2D 6）、甲苯磺丁脲（CYP 2C 9）、奥美拉唑（CYP 2C 19）以及阿普唑仑和咪达唑仑（CYP 3A）。羟基安非他酮形成被用作比安非他酮动力学更敏感的CYP 2B 6活性标志物。从已发表的中国和高加索受试者体内研究中获得经口给药和静脉给药（如可能）后观察到的血浆药物浓度-时间曲线和药代动力学参数。在Simcyp中生成的虚拟受试者与体内研究中使用的受试者在年龄、性别、剂量和（如可能）表型频率方面相匹配。中国人和高加索人的CYP 2C 19弱代谢型（PM）[中国人13%;高加索人2.4%]、CYP 2D 6 PM和中间代谢型（IM）[中国人PM 0.3%，IM 39%;高加索人PM <8%，IM <1%]、CYP 2C 19的肝脏丰度（平均值：中国人8 pmol/mg;高加索人14 pmol/mg）和肝脏重量（平均值：中国人1198 g;高加索人1603 g）。在两个种族组中，观察到的血浆药物浓度-时间曲线和体重标准化清除率的预测准确度合理（100%在2倍内; 89%在1.5倍内）。预测的非那西丁、甲苯磺丁脲、奥美拉唑、地昔帕明、咪达唑仑（静脉注射）、咪达唑仑（口服）、阿普唑仑中国人中，阿普唑仑（静脉注射）和阿普唑仑（口服）的清除率分别比白人低36、25、51、43、24、17、21和22%;观察到的清除率分别低28、2、75、42、19、62、20和21%。预测和观察到的羟基安非他酮的形成在白人中低于中国人（分别为6%和20%）。民族之间的差异是较少的体重normalizedforbodyweight. Results的本研究表明的模拟的基础上，机械生理为基础的药代动力学模型（PBPK）在预测的可能程度的任何差异的动力学的底物在中国和高加索人群所产生的人口，生理和遗传差异。
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval.We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies.Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator(A (R)) (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration-time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight-normalized clearances were compared between the ethnic groups.Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) [Chinese 13 %; Caucasian 2.4 %], CYP2D6 PMs and intermediate metabolizers (IMs) [Chinese PMs 0.3 %, IMs 39 %; Caucasian PMs 8 %, IMs < 1 %], the hepatic abundance of CYP2C19 (mean values: Chinese 8 pmol/mg; Caucasian 14 pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration-time profiles and weight-normalized clearances were predicted with reasonable accuracy (100 % within twofold; 89 % within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22 % lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21 % lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20 %, respectively). Differences between ethnic groups were less after normalization for body weight.The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences.