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: 10463665
• 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/10463665
• 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; 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.

项目摘要 这项工作的首要目标是改进对药物-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)。目前的资金 时期对代谢产物中间体复合体的作用机制有了新的认识 (MIC)的形成和基于数值的复杂酶动力学的新模型 接近了。在存在MIC形成、部分失活和非MIC时的DDI预测 Michaelis-Menten多重结合，现在用我们的新方法是可能的。这些新的结果 带来了新的问题和假设，以改善对TDIS的DDI预测，这是由于 顺序新陈代谢，以及也是激活剂的TDI。激活器要求型号包括 受害者-犯罪者-酶复合体。此外，很明显，顺序性 新陈代谢涉及形成的代谢物扩散出肝细胞。因此，我们正在 开发新的膜通透性限制动力学模型以改进预测 受害者PK。提出了三个具体目标。在目标1下，体外TDI分析和ADME数据 将会被收取。我们发布的数值方法将用于数据分析和TDI 模特儿。顺序新陈代谢和代谢产物向细胞外扩散的动力学将是 用新的共聚焦显微镜实验进行了评估。数据将使用Partial 微分方程式，以表征分析物水平随时间和整个细胞的距离。在……里面 大鼠肝脏的原位序贯代谢和空间分布将在大鼠肝脏切片中被量化 使用MALDI-FTMS。在目标2中，人和大鼠完全渗透或灌流受限的PBPK 将开发新的模型，包括开窗与不开窗的模型 血管系统、明显的膜、代谢和主要器官的主动运输。 这些模型将通过19种化合物的临床C-t曲线进行验证(酸、碱和 中性)，以及来自10种化合物的大鼠单次静脉注射剂量数据。在目标3中，体外数据来自于 AIM 1将被纳入来自AIM 2的新的PBPK模型框架。 将被预测，并将预测的好坏与当前的标准预测进行比较 方法：研究方法。拟议的研究将揭示TDI的机制和动力学，因为顺序 新陈代谢，激活，以及未知的过程。这项工作的更大意义在于 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。