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，在美国进行了33,000多个器官移植，过去增加了20％ 5年。器官移植需要终身免疫抑制以防止移植的排斥。 他克莫司，一种大环内酯类抗生素，是最有效的免疫抑制剂之一，具有> 90％的固体器官 作为维持免疫抑制的一部分，移植接受者接受了它。他克莫司有一个狭窄的 治疗窗口，其亚治疗水平使患者处于拒绝和超级治疗水平的危险中 导致毒性。除了明显的药代变异性外，还估计> 25％的患者 不适合其免疫抑制剂方案，显着提高了移植物的排斥和衰竭率 并增加美国医疗保健系统上的财务燃烧。因为移植接收者需要一生 免疫抑制，任何促进剂量和不遵守迅速检测的方法都是 出色的临床实用程序。 因为在护理点上无法确定他克莫司水平，所以检测非治疗水平 门诊环境是挑战。患者必须在例行前参加单独的实验室约会 后续访问或在访问当天提取的水平。在前者中，将一个额外的伯恩放在 患者参加额外的预约，而后者排除了患者之前对水平的分析 预约。药物管理的延迟或患者不合规的识别将患者置于 移植排斥反应（亚治疗水平）或药物相关毒性（上治疗水平）的风险。到 解决这个技术障碍，Affinergy计划开发出护理点的横向流量测定法 经常对他克莫司水平进行经常，准确且负担得起的监测。我们已经生成了 专有捕获试剂并确定了与纳摩尔亲和力结合的几个检测试剂候选者 克莫司。在第一阶段结束时，我们将拥有一个原型的横向流程测定法，其既定极限 定量。在第二阶段，我们将扩大评估的生产，优化性能特征，建立 存储条件，确定稳定性并使用移植受者血液样本评估我们的评估。 该项目的成功完成将导致改善接受他克莫司的患者的长期维护 为了免疫抑制并减轻患者和提供者的燃烧。