Novel assay to monitor Tacrolimus levels at the point of care

在护理点监测他克莫司水平的新方法

• 批准号: 10203792
• 负责人: Martyn Darby
• 金额: $ 73.5万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203792
• 关键词: Address; Affinity; Antibiotics; Appointment; Binding; Biological; Biological Assay; Blood; Blood specimen; Characteristics; Clinic; Clinical; Complex; Detection; Development; Dose; Drug Kinetics; Early identification; Evaluation; Financial Hardship; Freezing; Graft Rejection; Guidelines; Healthcare Systems; Immunosuppression; Immunosuppressive Agents; Institutes; Label; Laboratories; Libraries; Life; Liquid substance; Macrolides; Maintenance; Measurement; Measures; Medication Management; Methodology; Methods; Monitor; Organ Transplantation; Outpatients; Patient Appointment; Patient Noncompliance; Patients; Peptides; Performance; Pharmaceutical Preparations; Phase; Production; Provider; Reader; Reagent; Regimen; Reproducibility; Risk; Running; Sampling; Ships; Solid; Specificity; Specimen; Tacrolimus; Tacrolimus Binding Proteins; Testing; Therapeutic; Toxic effect; Transplant Recipients; United States; Validation; Visit; Whole Blood; base; cross reactivity; design; detection limit; dosage; follow-up; graft failure; improved; large scale production; lateral flow assay; lot production; nanomolar; novel; performance tests; point of care; point-of-care detection; prevent; prototype; rapid detection; receptor; scale up; stability testing; verification and validation

SUMMARY/ABSTRACT In 2016, over 33,000 organ transplants were performed in the United States, an increase of 20% over the past 5 years. Organ transplantation requires lifelong immunosuppression to prevent rejection of the transplant. Tacrolimus, a macrolide antibiotic, is one of the most effective immunosuppressants, with >90% of solid organ transplant recipients receiving it as part of their maintenance immunosuppression. Tacrolimus has a narrow therapeutic window, with sub-therapeutic levels putting patients at risk for rejection and supra-therapeutic levels leading to toxicity. In addition to significant pharmacokinetic variability, it is also estimated that >25% of patients are non-adherent to their immunosuppressant regimen, significantly increasing graft rejection and failure rates and increasing the financial burden on the US healthcare system. Because transplant recipients require a lifetime of immunosuppression, any methods that facilitate improved dosing and rapid detection of non-adherence are of great clinical utility. Because tacrolimus levels cannot be ascertained at the point of care, detection of non-therapeutic levels in the outpatient setting is challenging. Patients must either attend a separate lab appointment ahead of their routine follow-up visits or they have levels drawn on the day of their visit. In the former, an extra burden is placed on the patient to attend an additional appointment while the latter precludes analysis of levels prior to the patient’s appointment. Delays in medication management or identification of patient non-compliance place the patient at risk for graft rejection (sub-therapeutic levels) or drug-associated toxicities (supra-therapeutic levels). To address this technical hurdle, Affinergy plans to develop a point-of-care lateral flow assay that will enable frequent, accurate and affordable monitoring of tacrolimus levels. We have already generated a proprietary capture reagent and identified several detection reagent candidates that bind with nanomolar affinity to tacrolimus. At the conclusion of Phase I, we will have a prototype lateral flow assay with established limits of quantitation. In Phase II, we will scale up production of our assay, optimize performance characteristics, establish storage conditions, determine stability and evaluate our assay using transplant recipient blood specimens. Successful completion of this project will lead to improved long-term maintenance of patients receiving tacrolimus for immunosuppression and ease the burden on both patients and providers.

摘要/摘要 2016年，美国进行了超过3.3万例器官移植，比过去增加了20% 器官移植需要终生免疫抑制以防止移植排斥。 他克莫司是一种大环内酯类抗生素，是最有效的免疫抑制剂之一，对实体器官的影响>90% 移植受者接受他克莫司作为维持免疫抑制的一部分，其作用范围较窄。 治疗窗口，亚治疗水平的患者有排斥风险并处于超治疗水平 除了显着的药代动力学变异外，据估计 >25% 的患者也会出现毒性反应。 不遵守免疫抑制剂治疗方案，显着增加移植物排斥和失败率 并增加美国医疗保健系统的经济负担，因为移植接受者需要终生。 对于免疫抑制，任何有助于改善剂量和快速检测不依从性的方法都是 具有很大的临床实用性。 由于他克莫司水平无法在护理点确定，因此检测非治疗水平 门诊环境具有挑战性，患者必须在日常工作之前参加单独的实验室预约。 后续访视或在访视当天确定等级。如果是前者，就会给被访者带来额外的负担。 患者参加额外的预约，而后者排除了对患者之前的水平进行分析 药物管理的延误或发现患者不遵守规定会使患者陷入困境。 移植物排斥（亚治疗水平）或药物相关毒性（超治疗水平）的风险。 为了解决这一技术障碍，Affinergy 计划开发一种即时侧向层析检测，该检测将 能够频繁、准确且经济地监测他克莫司水平。 捕获试剂并鉴定了几种以纳摩尔亲和力结合的候选检测试剂 在第一阶段结束时，我们将有一个原型侧流分析，其限制为 在第二阶段，我们将扩大检测的生产规模，优化性能特征，建立 储存条件，确定稳定性并使用移植受者血液样本评估我们的测定。 该项目的成功完成将改善接受他克莫司的患者的长期维持 用于免疫抑制并减轻患者和提供者的负担。