Drug-drug interactions for antivirals with opioids and Narcan in a 5- organ human-on-a-chip model

抗病毒药物与阿片类药物和纳洛酮在 5 器官芯片模型中的药物相互作用

• 批准号: 10224388
• 负责人: James J Hickman
• 金额: $ 16.7万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-27 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224388
• 关键词: Acute; Age; Analgesics; Animal Experiments; Animal Model; Antiviral Agents; Blood; Brain Stem; Breathing; Bypass; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cells; Cellular Structures; Cessation of life; Chronic; Clinic; Clinical; Clinical Trials; Codeine; Collaborations; Communication; Community Developments; Complex; Development; Disease; Disease model; Dose; Drug Industry; Drug Interactions; Elements; Environment; Evaluation; Female; Fentanyl; Functional disorder; Funding; Future; Goals; Gold; Grant; Health; Heart Diseases; Human; Immune; Immunological Models; In Vitro; Infection; Kidney; Lead; Legal patent; Liver; Long-Term Effects; Mechanics; Methadone; Microelectrodes; Modeling; Morphine; Muscle; Myocardium; Naloxone; Narcan; Neurons; Nociceptors; Opioid; Opioid abuser; Organ; Organ Model; Organ failure; Outcome; Overdose; Pain; Parents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Physiology; Pre-Clinical Model; Publishing; Recovery; Role; Serum; Services; Skeletal Muscle; System; Therapeutic; Therapeutic Effect; Tissue Microarray; Tissue Model; Toxic effect; Translating; Translations; Treatment Efficacy; addiction; authority; base; body system; cantilever; clinical predictors; comorbidity; cooking; cost; drug candidate; drug development; drug discovery; drug efficacy; drug testing; human model; in vitro Model; individualized medicine; male; model development; monocyte; mu opioid receptors; novel; opioid overdose; personalized medicine; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; pre-clinical; preclinical study; response; screening; skills; success

Project Summary Addiction to pain medications, especially opiates, has become a major health problem and systems to guide the understanding of repeat overdose treatments are needed. Our proposal seeks to build overdose models for four drugs (fentanyl, methadone, codeine, and morphine) in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments such as Naloxone on overdose recovery, efficacy as well as off-target toxicity for cardiac, muscle, kidney and liver. We have developed a low cost system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. This system emulates the distribution of a parental compound and the formation of metabolites among all “organ” compartments and predicts potential toxicity and efficacy of drugs better than in vitro single human organ or animal models. We will develop two different overdose models for both male and female phenotypes based on nociceptors and Bӧtzinger Complex (BӧtC) neurons as they contain µ-opioid receptors but are thought to have different roles in response to overdose and treatment. We will also integrate functional immune components in the UH3 Phase that has been demonstrated to enable organ specific or systemic monocyte actuation. In addition, models for cardiomyopathy and an infection model will be utilized to more accurately represent the effects of therapeutics on comorbidities. We will establish a PKPD in vitro model of overdose and treatment to enable prediction in clinical environments for a range of variables including age and drug-drug interactions. Once established the system could be used to evaluate novel pain therapeutics for efficacy and off-target toxicity as well as additional overdose treatments in future studies. Interconnected systems with continuous recirculation of a blood surrogate allows both the parent compound and its metabolites to be evaluated in the same system since it is a low volume platform. This interconnected system is better suited for preclinical drug testing than single organ systems for the same reason that human and animal models are currently the gold standards for toxicity and efficacy determination as they allow communication between the organ systems in the body. To construct a well defined system we will use a common serum free medium with microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts of organ function. UCF and Hesperos in collaboration with clinicians seek to radically change established practice in drug discovery by bypassing animal experiments and extensive clinical trials to provide treatments for diseases and clinical conditions such as overdose. We have already been working with regulatory authorities to prepare for eventual acceptance of the systems for regular use in INDs. Since Hesperos is already offering multi-organ evaluations as a service to the pharmaceutical industry and clinicians there is a direct translational element in the proposal.

项目摘要 对止痛药的成瘾，特别是优化，已成为指导的主要健康问题和系统 需要对重复过量治疗的理解。我们的建议旨在建立过量模型 多器官系统中的四种药物（芬太尼，甲酮，可待因和吗啡），并评估急性和 过量治疗（例如纳洛酮）对过量恢复的重复剂量或慢性作用 作为心脏，肌肉，肾脏和肝脏的脱靶毒性。我们已经使用人类开发了低成本系统 Pumpless多器官平台中的细胞，该平台允许连续再循环血液替代物，最多可达28 天。该系统模拟了父母化合物的分布以及所有人之间的代谢形成 “器官”室和预测药物的潜在毒性和效率比体外单人体器官更好 或动物模型。我们将针对基于男性和女性表型开发两种不同的过量模型 在伤害感受器和bnameceptors和bnamecepter复合物（bnameceptors）神经元中含有µ-阿片受体，但被认为是 对过量服用和治疗具有不同的作用。我们还将整合功能性免疫成分 在已证明可以使器官特异性或全身单核细胞激活的UH3相中。在 此外，将使用心肌病和感染模型的模型来准确地表示 治疗对合并症的影响。我们将建立一个PKPD的体外过量模型和治疗 在临床环境中启用一系列变量的预测，包括年龄和药物相互作用。一次 建立该系统可用于评估新颖的疼痛疗法以提高效率和脱靶毒性为 以及未来研究中的其他过量治疗。互连系统，连续再循环 血液替代物允许在同一系统中评估母体化合物及其代谢物 由于它是一个低音量平台。该互连系统比临床前药物测试更适合 单器官系统的原因是人类和动物模型目前是金标准的原因 毒性和效率确定，因为它们允许体内器官系统之间进行通信。到 构建一个定义明确的系统，我们将使用带有微电极阵列的常见无血清培养基和 集成在芯片上的悬臂系统，可以进行无创的电子和机械读数 器官功能。 UCF和Hesperos与临床医生合作寻求从根本上改变既定的实践 在药物发现中，通过绕过动物实验和广泛的临床试验来发现疾病的治疗方法 和临床状况，例如过量。我们已经与监管机构合作准备 用于事件接受系统，以定期使用IND。由于Hesperos已经提供了多器官 评估作为制药行业和临床医生的服务，有直接的翻译因素 提案。