Overcoming the shortcomings of the extended-clearance concept: a framework for developing a physiologically-based pharmacokinetic (PBPK) model to select drug candidates involving transporter-mediated clearance
Overcoming the shortcomings of the extended-clearance concept: a framework for developing a physiologically-based pharmacokinetic (PBPK) model to select drug candidates involving transporter-mediated clearance
复制标题
克服延长清除概念的缺点：开发基于生理学的药代动力学（PBPK）模型的框架，以选择涉及转运蛋白介导的清除的候选药物
DOI：
10.1080/17425255.2021.1912012
复制
发表时间：
2021
影响因子：
4.3
通讯作者：
Yurong Lai
中科院分区：
文献类型：
--
作者：
Xiaomin Liang;Yurong Lai
摘要引言：当在药物发现阶段只有动物数据和体外人体参数可用时，人体药代动力学（PK）预测对经历转运蛋白介导清除的候选药物可能是一个重大挑战。涵盖的领域：扩展清除概念（ECC）包括肝脏摄取、被动扩散、代谢和胆汁分泌过程，已适用于确定肝脏清除和药物相互作用（DDI）的速率决定过程。然而，由于ECC是从充分搅拌的模型中推导出来的，并且没有将肝脏视为药物分布器官来反映肝脏和血浆之间药物浓度的时间依赖性变化，因此它可能被滥用于药物发现中的化合物选择。专家观点：PBPK模型由一组药物质量平衡微分方程组成，可以克服ECC在预测人体PK方面的不足。IVIVE模型和比例因子的可预测性、相关性和可靠性必须使用猴体内测量的肝脏浓度或已知转运蛋白抑制剂的DDI数据或两者来验证。结合体外人数据和从经验证的猴PBPK模型获得的SF的人PBPK模型可用于药物发现阶段的化合物选择。
ABSTRACT Introduction:Human pharmacokinetic (PK) prediction can be a significant challenge to drug candidates undergoing transporter-mediated clearance, when only animal data and in vitro human parameters are available in the drug discovery stage. Areas covered:The extended clearance concept (ECC) that incorporates the processes of hepatic uptake, passive diffusion, metabolism and biliary secretion has been adapted to determine the rate-determining process of hepatic clearance and drug-drug interactions (DDIs). However, since the ECC is derived from the well-stirred model and does not consider the liver as a drug distribution organ to reflect the time-dependent variation of drug concentrations between the liver and plasma, it can be misused for compound selection in drug discovery. Expert opinion:The PBPK model consists of a set of differential equations of drug mass balance, and can overcome the shortcomings of the ECC in predicting human PK. The predictability, relevance and reliability of the model and the scaling factors for IVIVE must be validated using either the measured liver concentrations or DDI data with known transporter inhibitors, or both, in monkeys. A human PBPK model that incorporates in vitro human data and SFs obtained from the validated monkey PBPK model can be used for compound selection in the drug discovery phase.
影响因子：
3.8
作者：
Yang K;Guo C;Woodhead JL;St Claire RL 3rd;Watkins PB;Siler SQ;Howell BA;Brouwer KLR
通讯作者：
Brouwer KLR