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

• 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
• 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

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 Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market between 1999 and 2003 were associated with DDIs.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）。与复方用药相关的 DDI 的流行率 老年人中这一比例约为 80%。 DDI 相关的 ADR 可以通过减少 治疗效果或增加药物的毒性。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 十亿美元。此外，约50%的药物出于安全原因从美国市场撤回 1999 年至 2003 年间与 DDI 相关。这对于复杂的 DDI 尤其重要，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。由于 DDI 无法在不进行预防的情况下预防 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，有 在药物开发过程中需要仔细计划临床前和临床 DDI 研究。然而，目前在 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）。这项提议的技术 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 药理学（QSP）模型可生成更具预测性的临床前药物数据。该 SBIR 第一阶段项目将 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。内源性促肝因子是 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。将使用高通量筛选亲肝因子 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。由此产生的 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 驱动持续的 DME 和转运蛋白基因表达和活性，以进行 DMPK-DDI 研究。 Javelin 的 DMPK- 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。