Novel clinical assay to rapidly monitor posaconazole levels in plasma

快速监测血浆中泊沙康唑水平的新型临床检测方法

• 批准号: 10246670
• 负责人: JONATHAN A HODGES
• 金额: $ 29.45万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246670
• 关键词: Adoption; Affinity; Americas; Antifungal Agents; Aspergillus; Bacteriophages; Binding; Biological Assay; Buffers; Candida; Candida albicans; Cessation of life; Clinical; Clinical Chemistry; Communicable Diseases; Complex; Cryptococcus; Cytochrome P450; Detection; Dose; Drug Monitoring; Endogenous Factors; Ensure; Enzymes; Exposure to; FDA approved; Guidelines; HIV; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; High Pressure Liquid Chromatography; Hospital Mortality; Immobilization; Immunocompromised Host; Individual; Infection; Institutes; Institution; Laboratories; Life; Mass Spectrum Analysis; Measurement; Measures; Monitor; Mycoses; Output; Pathway interactions; Patients; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Phase; Plasma; Production; Prophylactic treatment; Reagent; Resistance development; Risk; Sampling; Signal Transduction; Sirolimus; Societies; Sterols; Technology; Tenofovir; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Triazoles; base; commercialization; cost; detection limit; effective therapy; high risk; individual variation; infection risk; magnetic beads; mortality; novel; oropharyngeal thrush; posaconazole; pressure; prevent; protein aminoacid sequence; rapid test; reagent testing; resistant strain; routine care; scale up; validation studies; verification and validation

SUMMARY/ABSTRACT Invasive fungal infections (IFIs) contribute to more than 1.5 million deaths worldwide each year and pose a serious and continuous health risk to immunocompromised individuals. The rate of mortality associated with IFI is high, and there are only four major classes of antifungal drugs available to treat IFI, of which the triazoles find greatest use. Posaconazole (PCZ; Noxafil®) is the newest triazole and is the broadest spectrum, demonstrating activity against Aspergillus, Candida and Cryptococcus species. PCZ is indicated in the U.S. for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk for these infections, including hematopoietic stem cell transplant recipients, those with hematologic malignancies, and other immunocompromised patients. It is also indicated for treatment of oropharyngeal candidiasis (OTC), a condition common among HIV patients. While PCZ is not associated with significant toxicities, it displays high inter- and intra-individual variation in plasma drug concentrations, with subtherapeutic levels associated with poor efficacy. There is significant evidence to demonstrate that inadequate exposure to antifungals is independently associated with increased hospital mortality, and the Infectious Diseases Society of America recommends therapeutic drug monitoring (TDM) of PCZ to ensure adequate treatment. Unfortunately, there are currently no FDA approved assays available for performing PCZ TDM. Available assays remain limited to institutions or laboratories that have developed in-house laboratory-developed tests that rely on high- performance liquid chromatography (HPLC) or HPLC with mass spectrometry. These complex assays are expensive and lack harmonization, making it impossible to compare results from one test to the next. Most importantly, the turnaround time can range from several days to a week, making routine dose adjustments based on timely results impossible. Affinergy plans to develop a novel locking assay for the direct measurement of PCZ levels in plasma that is compatible with common clinical chemistry analyzers to facilitate routine TDM. Our assay with its lower cost and rapid turnaround will open access to a majority of patients to ensure that therapeutic levels are achieved to prevent life-threatening breakthrough infections and help control the rise of resistant strains.

总结/摘要 侵袭性真菌感染（IFIs）每年在全球造成超过150万人死亡， 对免疫功能低下的个体造成严重和持续的健康风险。与IFI相关的死亡率 含量很高，只有四种主要的抗真菌药物可用于治疗IFI，其中三唑类药物是其中之一 最大的用途。泊沙康唑（PCZ; Noxafil®）是最新的三唑类药物，具有最广泛的谱， 对曲霉属、念珠菌属和隐球菌属的活性。 PCZ在美国适用于预防以下患者的侵袭性曲霉菌和念珠菌感染： 这些感染的高风险，包括造血干细胞移植受者，血液病患者， 恶性肿瘤和其他免疫功能低下的患者。它还适用于治疗口咽疾病 念珠菌病（OTC）是HIV患者中常见的一种疾病。虽然PCZ与显著的 毒性，它显示出高的血浆药物浓度的个体间和个体内变异， 与疗效差相关的水平。有大量证据表明， 抗真菌药物与医院死亡率增加独立相关， 美国建议对PCZ进行治疗药物监测（TDM），以确保PCZ得到充分治疗。不幸的是， 目前还没有FDA批准的用于进行PCZTDM的测定法。可用的检测方法仍然有限 已经开发出内部实验室开发的测试的机构或实验室， 高效液相色谱（HPLC）或HPLC与质谱联用。这些复杂的测定是 昂贵且缺乏统一性，使得无法将一个测试的结果与另一个测试的结果进行比较。最 重要的是，周转时间可以从几天到一周不等， 及时的结果是不可能的Affinergy计划开发一种新的锁定测定法，用于直接测量 血浆中的PCZ水平，与常见的临床化学分析仪兼容，以便于常规 TDM。我们的检测以其较低的成本和快速的周转将开放给大多数患者，以确保 达到治疗水平，以防止危及生命的突破性感染，并帮助控制 耐药菌株