Microsampling Assays for Immunosuppressive Drugs in Children

儿童免疫抑制药物的微量取样测定

基本信息

批准号：
10447731
负责人：
STEPHEN R MASTER
金额：
$ 21.84万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2021-07-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447731
关键词：
Achievement Adult Autoimmune Autoimmune Diseases Biological Assay Blood Blood Volume Blood capillaries Blood specimen Bone Marrow Stem Cell Transplantation CLIA certified COVID-19 Cannabinoids Cefepime Chemistry Child Childhood Clinic Clinical Clinical Research Collection Crohn&apos s disease Cyclosporine Development Devices Disease Dose Drug Monitoring Drug usage Eczema Ensure Erythrocytes FDA approved Family Flare Foundations Goals Head Home Immunoassay Immunocompromised Host Immunosuppressive Agents In Vitro Individual Infection Laboratories Life Liquid Chromatography Measures Medicine Methods Muscle Needles Nephrotic Syndrome Organ Outcome Outpatients Painless Patients Pharmaceutical Preparations Population Psoriasis Reporting Research Rewards Rheumatoid Arthritis Risk Sampling Shipping Sirolimus Solid Tacrolimus Techniques Therapeutic Therapeutic immunosuppression Toxic effect Transplant Recipients Validation Vancomycin Veins Venous Venous blood sampling Visit Voriconazole Whole Blood Work autoinflammatory deltoid muscle family burden immunosuppressed improved infection risk innovation multidisciplinary novel organ transplant rejection pediatric patients prevent programs routine care sample collection tandem mass spectrometry validation studies

项目摘要

PROJECT SUMMARY Immunosuppressive therapy is the foundation of successful long-term outcomes after solid organ and bone marrow/stem cell transplants and as a treatment for various auto-inflammatory conditions, including rheumatoid arthritis, eczema, psoriasis, Crohn's disease, and nephrotic syndrome in adults and children. The optimal blood concentrations of these drugs are critical to minimize toxicity and to prevent rejection in transplant recipients. These drugs require frequent and often life-long therapeutic drug monitoring (TDM) to ensure that dosing maintains the optimal therapeutic concentrations. Current TDM (clinical standard) used for the dosing guidance of cyclosporine A (CYA), tacrolimus (TAC), and sirolimus (SIR) are derived from whole blood immunoassays or liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. This requires immunosuppressed individuals to go to outpatient laboratories for phlebotomy, potentially increasing their risk of acquiring infections. The development of an easy-to-use, small volume, blood sampling approach can facilitate home sampling and reduce the burden on pediatric patients and their families. Current TDM requires 0.5 to 1.0 mL of whole blood, typically via phlebotomy. Volumetric absorptive microsampling (VAMS) with Mitra devices or Tasso-M20 devices allows for the collection of a fixed small volume of blood (e.g., 20 µL) from a capillary needle without the need for phlebotomy. Clinical validation studies for CYA, TAC, and SIR with Mitra devices in adults were recently reported. While one study showed a good correlation for TAC analysis, the other study showed inconsistency with sample collection using Mitra devices. Therefore, the potential utility of Mitra devices for routine TDM is uncertain. FDA-approved Tasso-M20 devices allow for an accurate, precise, painless, and consistent collection of a fixed small volume of blood. However, the implementation of Tasso-M20 devices into the clinical setting for TDM requires both analytical and clinical validation. The objectives of the proposed Microsampling Assays for Immunosuppressive Drugs in childrEN (MAIDEN) study is to: 1) validate Tasso-M20 VAMS LC-MS/MS assays for CYA, TAC, and SIR, 2) evaluate in vitro stability of CYA, TAC, and SIR in Tasso-M20 devices under the conditions of shipping and storage, 3) clinically validate Tasso-M20 VAMS LC-MS/MS assays for CYA, TAC, and SIR against current venous whole blood TDM immunoassays in pediatric patients, and 4) confirm the stability of CYA, TAC, and SIR in Tasso-M20 VAMS clinical samples under the conditions of shipping and storage. If successful, this research will enable the use of the microsampling method for TDM in the clinical setting (obviating the need for invasive phlebotomy), and at home (reducing the burden on families to bring the immunosuppressed children out of the home for routine TDM), and revolutionize remote sampling for TDM of immunosuppressant drugs in children and adults.

项目概要免疫抑制治疗是实体器官和骨骼治疗后成功的长期结果的基础骨髓/干细胞移植以及治疗各种自身炎症性疾病，包括类风湿病成人和儿童的关节炎、湿疹、牛皮癣、克罗恩病和肾病综合症的最佳血液。这些药物的浓度对于最大限度地减少毒性和防止移植受者的排斥反应至关重要。这些药物需要频繁且通常是终生的治疗药物监测 (TDM)，以确保剂量维持当前用于剂量指导的最佳治疗浓度。环孢素 A (CYA)、他克莫司 (TAC) 和西罗莫司 (SIR) 源自全血免疫测定或液相色谱-串联质谱 (LC-MS/MS) 检测需要免疫抑制。个人前往患者实验室进行放血，可能会增加感染的风险。开发一种易于使用、小体积的血液采样方法可以方便家庭采样和减轻儿科患者及其家人的负担。目前的 TDM 需要 0.5 至 1.0 mL 全血，通常通过使用 Mitra 设备或 Tasso-M20 设备进行体积吸收微量取样 (VAMS)。允许从毛细管针采集固定的少量血液（例如 20 µL），无需最近进行了成人放血术的 CYA、TAC 和 SIR 的临床验证研究。据报道，虽然一项研究显示 TAC 分析具有良好的相关性，但另一项研究却显示出不一致。使用 Mitra 设备进行样本采集因此，Mitra 设备对于常规 TDM 的潜在效用是 FDA 批准的 Tasso-M20 设备可实现准确、精确、无痛且一致的采集。然而，Tasso-M20 装置的实施进入临床环境。 TDM 需要分析和临床验证所提议的微量采样测定的目标。儿童免疫抑制药物 (MAIDEN) 研究旨在：1) 验证 Tasso-M20 VAMS LC-MS/MS 检测对于 CYA、TAC 和 SIR，2) 在 Tasso-M20 装置中评估 CYA、TAC 和 SIR 的体外稳定性运输和储存条件，3) 经过临床验证的 Tasso-M20 VAMS LC-MS/MS 检测，用于 CYA、TAC、和 SIR 对比当前儿科患者静脉全血 TDM 免疫测定，以及 4) 确认稳定性 Tasso-M20 VAMS 临床样品在运输和储存条件下的 CYA、TAC 和 SIR。成功后，这项研究将使 TDM 的微采样方法能够在临床环境中使用（消除了侵入性静脉切开术的需要），以及在家里（减轻了家庭携带血液的负担）免疫抑制儿童离开家进行常规 TDM），并彻底改变了 TDM 的远程采样儿童和成人的免疫抑制剂。