DDI-on-a-chip: an optimized liver microphysiological system and microenvironment for complex drug-drug interaction studies

DDI-on-a-chip：用于复杂药物相互作用研究的优化肝脏微生理系统和微环境

基本信息

批准号：
10324897
负责人：
Murat Cirit
金额：
$ 25.96万
依托单位：
JAVELIN BIOTECH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2023-03-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324897
关键词：
Adsorption Affect Biological Assay Cell Culture Techniques Cells Chemicals Clinical Complex Data Decision Making Development Drug Costs Drug Exposure Drug Interactions Drug Kinetics Drug Modelings Drug toxicity Elderly Engineering Enzyme Inhibition Enzymes Evaluation Event Fee-for-Service Plans Gene Expression Growth Factor Guidelines Health Healthcare Hepatic Hepatocyte Hospitalization Human In Vitro Lead Liver Metabolism Modeling Morbidity - disease rate Nutrient Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phenotype Physiological Physiology Polypharmacy Population Pre-Clinical Model Preclinical Drug Development Predictive Value Prevalence Process Property Recommendation Reproducibility Risk Safety Signal Transduction Small Business Innovation Research Grant Somatotropin System Technology Time Toxic effect Treatment Efficacy United States Withdrawal adverse drug reaction base clinical effect clinical predictors clinically relevant cost cost effective cost estimate design drug development drug metabolism experimental study fetal first-in-human improved interest microphysiology system novel novel therapeutics perpetrators pharmacokinetic model polycarbonate pre-clinical prevent screening transcription factor

项目摘要

Project Summary Drug-drug interactions (DDIs), caused by the administration of multiple drugs simultaneously (i.e polypharmacy), can lead to adverse drug reactions (ADRs). The prevalence of polypharmacy-related DDIs among older adults is ~80%. DDI-related ADRs can cause profound clinical effects, either by reducing therapeutic efficacy or increasing the toxicity of drugs. In the United States (US), ADRs are common, causing 1.1% of annual hospital admissions, and expensive with associated annual costs estimated between 30-180 billion dollars. Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market between 1999 and 2003 were associated with DDIs. This is especially relevant for complex DDIs which include metabolism-transporter interplay, time-dependent and mixed inhibition/induction of drug-metabolizing enzymes (DMEs) and transporters, and metabolite-based inhibition/induction. As DDIs cannot be prevented without comprehensive drug pharmacokinetic (PK) data to guide medication adjustments according to DDI risks, there is a need for carefully planned preclinical and clinical DDI studies during drug development. However, current in vitro preclinical liver PK models, including microphysiological systems (MPSs), suffer from important functional limitations such as expression of a fetal phenotype, low expression levels of drug-metabolizing enzymes and transporters, and rapid phenotypic dedifferentiation (i.e., short-term culture systems). This proposed technology will be especially applicable for drugs with complex DDI liability including time-dependent induction of DMEs and transporters. Javelin’s overall strategy is to develop microphysiological systems (MPSs) optimized for drug metabolism and pharmacokinetics (DMPK) studies including DDIs to be used in combination with our quantitative systems pharmacology (QSP) models to generate more predictive preclinical drug data. This SBIR phase I project will establish the optimal cellular and hepatotropic factor microenvironment to drive long-term, physiologically- relevant expression, and activity of liver DMEs and transporters. The endogenous hepatotropic factors will be selected for their ability to maintain liver cell health and drive the transcription factor signaling networks that regulate DME and transporter gene expression. The hepatotropic factors will be screened using a high- throughput fractional factorial analysis approach and optimized in Javelin’s polycarbonate (i.e., PDMS-free to minimize nonspecific drug adsorption), millifluidic, recirculating MPS engineered for DMPK studies. The resulting medium supplement, “DMPK-optimal” will be the first chemically-defined, xenoprotein-free supplement designed to drive sustained DME and transporter gene expression and activity for DMPK-DDI studies. Javelin’s DMPK- DDI platform will be provided as a low-cost, commercial-available product to pharmaceutical companies interested in generating comprehensive, accurate, human-based PK data to better inform their drug development process and design of first in-human (FIH) trials.

项目概要药物间相互作用 (DDI)，由同时服用多种药物引起（即：多药治疗）可能导致药物不良反应（ADR）与多药治疗相关的 DDI 的流行。在老年人中，约 80% 的 DDI 相关 ADR 可以通过减少不良反应来引起深远的临床影响。治疗效果或增加药物毒性在美国，ADR 很常见，导致。占每年入院人数的 1.1%，且费用昂贵，相关年度费用估计在 30-180 之间此外，大约 50% 的药物出于安全原因从美国市场撤回。 1999 年至 2003 年间的数据与 DDI 相关，这对于复杂的 DDI 尤为重要，其中包括。代谢-转运蛋白相互作用、药物代谢酶的时间依赖性和混合抑制/诱导（DME）和转运蛋白，以及基于代谢物的抑制/诱导，因为 DDI 是无法预防的。全面的药物药代动力学 (PK) 数据可根据 DDI 风险指导药物调整，然而，在药物开发过程中需要仔细计划临床前和临床 DDI 研究。体外临床前肝脏 PK 模型，包括微生理系统 (MPS)，受到重要功能的影响限制，例如胎儿表型的表达、药物代谢酶的低表达水平和转运蛋白和快速表型去分化（即短期培养系统）。将特别适用于具有复杂 DDI 责任的药物，包括 DME 的时间依赖性诱导和运输者。 Javelin 的总体战略是开发针对药物代谢优化的微生理系统 (MPS) 和药代动力学 (DMPK) 研究，包括与我们的定量系统结合使用的 DDI 该 SBIR 第一阶段项目将使用药理学 (QSP) 模型生成更具预测性的临床前药物数据。建立最佳的细胞和促肝因子微环境，以驱动长期的、生理上的肝脏 DME 和转运蛋白的相关表达和活性将是内源性促肝因子。因其维持肝细胞健康和驱动转录因子信号网络的能力而被选中调节 DME 和转运蛋白基因表达将使用高通量筛选。吞吐量部分因子分析方法并在 Javelin 的聚碳酸酯（即不含 PDMS 的聚碳酸酯）中进行了优化最大限度地减少非特异性药物吸附）、微流体、再循环 MPS，专为 DMPK 研究而设计。培养基补充剂，“DMPK-optimal”将是第一个化学成分明确、不含异种蛋白的补充剂驱动 DMPK-DDI 研究中持续的 DME 和转运蛋白基因表达和活性。 DDI平台将作为低成本、可商用的产品提供给制药公司有兴趣生成全面、准确、基于人的 PK 数据，以更好地为他们的药物开发提供信息首次人体 (FIH) 试验的流程和设计。