Improving prediction of drug interactions mediated by time-dependent inhibitors

改进对时间依赖性抑制剂介导的药物相互作用的预测

• 批准号: 10263382
• 负责人: Kenneth Ray Korzekwa
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263382
• 关键词: Acids; Active Biological Transport; Binding; Biological Assay; CYP3A4 gene; Cell Membrane Permeability; Cells; Clinic; Clinical; Complex; Confocal Microscopy; Coumarins; Cytochrome P450; Data; Data Analyses; Development; Diazepam; Differential Equation; Diffusion; Dose; Drug Interactions; Drug Kinetics; Enzyme Kinetics; Enzymes; Funding; Goals; Hepatocyte; Human; Image; Imaging Techniques; In Situ; In Vitro; Kinetics; Literature; Liver; MDCK cell; Mediating; Membrane; Metabolism; Methods; Mibefradil; Modeling; Multienzyme Complexes; Organ; Paroxetine; Perfusion; Permeability; Pharmaceutical Preparations; Process; Publishing; Rattus; Ritonavir; Rodent Model; Slice; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Ticlopidine; Time; Validation; Work; absorption; base; drug development; drug discovery; drug disposition; experimental study; human model; improved; in vivo; in vivo Model; inhibitor/antagonist; mathematical model; nile red; novel; perpetrators; physiologically based pharmacokinetics

Project Summary The overarching goal of this work is to improve predictions of drug-drug interactions (DDI) due to time dependent inactivation (TDI) of cytochrome P450 (CYP) enzymes. The current funding period has resulted in new understandings on mechanisms of metabolite intermediate complex (MIC) formation, and novel models for complex enzyme kinetics based on numerical approaches. DDI predictions in the presence of MIC formation, partial inactivation, and non- Michaelis-Menten multiple binding, are now possible with our new methods. These new results have led us to new questions and hypotheses for improving DDI predictions for TDIs due to sequential metabolism, and TDIs that are also activators. Activators require models that include victim-perpetrator-enzyme complexes. Additionally, it has become clear that sequential metabolism involves diffusion of formed metabolites out of hepatocytes. Therefore, we are developing novel membrane permeability-limited dynamic models for improved predictions of victim PK. Three specific aims are proposed. Under Aim 1, in vitro TDI assays and ADME data will be collected. Our published numerical methods will be used for data analysis and TDI modeling. Kinetics of sequential metabolism and metabolite diffusion out of the cell will be evaluated with novel confocal microscopy experiments. Data will be modeled with partial differential equations to characterize analyte levels over time and distance across the cell. In situ sequential metabolism and spatial distribution in rat liver will be quantified in rat liver slices with MALDI-FTMS. In Aim 2, human as well as rat fully permeability- or perfusion-limited PBPK models will be developed, with novel incorporation of fenestrated vs. non-fenestrated vasculature, explicit membranes, and metabolism and active transport in/out of major organs. The models will be validated with clinical C-t profiles of 19 compounds (mix of acids, bases, and neutrals), and rat single IV dosing data from 10 compounds. In aim 3, in vitro data obtained from Aim 1 will be incorporated into the new PBPK model framework from Aim 2. Clinical and rat DDI will be predicted, and goodness of prediction will be compared to current standard prediction methods. The proposed studies will uncover mechanisms and kinetics of TDI due to sequential metabolism, activation, and as yet unknown processes. The larger significance of this work lies in marked improvement in the prediction of human drug disposition (absorption, distribution, and elimination) for drug discovery and development.

项目概要 这项工作的总体目标是改进对药物相互作用 (DDI) 的预测 细胞色素 P450 (CYP) 酶的时间依赖性失活 (TDI)。目前资金情况 时期对代谢中间体复合物的机制产生了新的认识 （MIC）的形成，以及基于数值的复杂酶动力学的新模型 接近。存在 MIC 形成、部分失活和非失活情况下的 DDI 预测 现在我们的新方法可以实现 Michaelis-Menten 多重结合。这些新成果 由于以下原因，我们提出了新的问题和假设，以改进 TDI 的 DDI 预测 顺序代谢和 TDI 也是激活剂。激活器需要的模型包括 受害者-肇事者-酶复合物。此外，很明显，顺序 代谢涉及形成的代谢物从肝细胞中扩散出来。因此，我们是 开发新型膜渗透性有限动态模型以改进预测 受害者PK。提出了三个具体目标。在目标 1 下，体外 TDI 测定和 ADME 数据 将被收集。我们发布的数值方法将用于数据分析和 TDI 造型。连续代谢和代谢物扩散出细胞的动力学将是 通过新颖的共焦显微镜实验进行评估。数据将通过部分建模 微分方程来表征分析物水平随时间和细胞距离的变化。在 大鼠肝脏的原位顺序代谢和空间分布将在大鼠肝脏切片中量化 与 MALDI-FTMS。在目标 2 中，人类以及大鼠完全通透性或灌注受限的 PBPK 将开发模型，将有窗与无窗的新颖结合 脉管系统、外显膜、代谢和主要器官的主动运输。 该模型将通过 19 种化合物（酸、碱和化合物的混合物）的临床 C-t 曲线进行验证。 中性剂），以及 10 种化合物的大鼠单次静脉注射给药数据。在目标 3 中，体外数据来自 目标 1 将被纳入目标 2 的新 PBPK 模型框架中。临床和大鼠 DDI 将进行预测，并将预测的优度与当前标准预测进行比较 方法。拟议的研究将揭示 TDI 的机制和动力学 新陈代谢、激活和迄今未知的过程。这项工作更大的意义在于 在预测人类药物处置（吸收、分布和 消除）用于药物发现和开发。