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.

项目摘要 这项工作的总体目标是改善药物相互作用（DDI）的预测， 细胞色素P450（CYP）酶的时间依赖性失活（TDI）。现行拨款 对代谢中间体复合物的作用机制有了新的认识 (MIC)形成，和新的模型，复杂的酶动力学的基础上，数值 接近。存在MIC形成、部分失活和非 Michaelis-Menten多重结合，现在可以用我们的新方法。这些新结果 导致我们提出了新的问题和假设，以改善TDI的DDI预测， 顺序代谢，以及也是激活剂的TDI。激活器需要的模型包括 受害者-犯罪者-酶复合体此外，很明显， 代谢涉及形成的代谢物扩散出肝细胞。因此我们 开发新的膜渗透性限制的动态模型，以改进对 受害人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。我们公布的数值方法将用于数据分析和TDI 建模将描述连续代谢和代谢物扩散出细胞的动力学。 用新的共聚焦显微镜实验进行评估。数据将采用部分 微分方程来表征细胞内分析物水平随时间和距离的变化。在 将在大鼠肝切片中定量大鼠肝中的原位顺序代谢和空间分布 MALDI-FTMS在目标2中，人以及大鼠完全渗透性或灌注限制性PBPK 将开发模型，并将开孔与非开孔进行新的合并 血管系统、外膜和代谢以及主要器官的主动转运。 该模型将用19种化合物（酸、碱和苯甲酸的混合物）的临床C-t曲线进行验证。 中性）和来自10种化合物的大鼠单次IV给药数据。在目标3中，从以下获得的体外数据： 目标1将纳入目标2的新PBPK模型框架。临床和大鼠DDI 将被预测，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，由于顺序 代谢、活化和未知过程。这项工作更大的意义在于 在预测人类药物处置（吸收，分布， 用于药物发现和开发。