Pharmacokinetics/Pharmacodynamics (PK/PD) Core

药代动力学/药效学 (PK/PD) 核心

• 批准号: 8866444
• 负责人: BARBARA R GRUBB
• 金额: $ 36.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866444
• 关键词: Affect; Animals; Chronic Obstructive Airway Disease; Clinical; Coughing; Deposition; Diagnostic Imaging; Drug Kinetics; Engineering; Exhalation; Heterogeneity; Human; Hydration status; Image; Inflammation; Intervention; Irrigation; Label; Lung; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modeling; Movement; Mucociliary Clearance; Mucolytics; Mucous body substance; Mus; Obstructive Lung Diseases; Patients; Pharmaceutical Preparations; Pharmacodynamics; Positron-Emission Tomography; Research Personnel; Sampling; Shapes; Site; Sputum; Structure; Surface; Techniques; Time; Uncertainty; airway obstruction; airway surface liquid; human subject; in vivo; novel; particle; radiotracer; response; single photon emission computed tomography

The PK/PD Core will provide 1) pharmacokinetic (PK) measurements of drug concentrations over time in airway surface liquid (ASL) from all three projects and 2) in-vivo pharmacodynamic (PD) measurements of mucociliary and cough clearance (MCC/CC) for the animal and human projects (Projects II and 111). 1. Pharmacokinetics. The pharmacological activities of drugs that affect mucus hydration are a reflection of their concentrations on airway surfaces. Measuring airway drug concentrations in human subjects is difficult using traditional methods. Bronchoscopic lavages suffer from variable dilutions and uncertainties about site sampled, and sputum likely reflects an abnormal secretion that originates primarily from large airway surfaces. Accordingly, we will develop mass spectrometric methods to accurately measure ASL concentrations of drugs, drug metabolites, and markers of ASL dilution that can be applied both to non-invasive airway samples such as exhaled breath condensate (EBC) and to other ASL samples obtained from all three projects. 2. Pharmacodynamics. Quantifying the response of mucociliary function to treatments targeted for chronic obstructive airways disease requires accurate, sensitive in-vivo measurements of MCC/CC for both animal and human models. Accordingly we will: a. Measure mucociliary clearance in mice by tracking tracheal velocities of fluorescently labeled beads for baseline and drug interventions that parallel those in the clinical projects. b. Measure MCC/CC in human subjects using techniques that standardize radiotracer deposition. Both baseline MCC/CC and the effects of mucolytic treatments will be assessed as described in Project 111. Measures of airways obstruction, ciliary dependent clearance (MCC), cough-dependent clearance (CC), and novel endpoints to describe heterogeneity of clearance will be made available to Project investigators. c. Engineer and produce novel particles of controlled size and shape for deposition on airway surfaces that 1) accurately track the movement of mucus from the lung and 2) permit multi-modal imaging (e.g. single photon emission computed tomography, positron emission tomography [PET], or MRI) to better delineate the degree and site of MCC abnormalities within the lungs of patients when combined with diagnostic imaging of lung structure (CT and MRI) and inflammation (PET).

PK/PD核心将提供1）药代动力学（PK）的测量，随着时间的流逝 来自所有三个项目的气道表面液体（ASL）和2）体内药效学（PD）测量 动物和人类项目（项目II和111）的粘毛和咳嗽清除（MCC/CC）。 1。药代动力学。影响粘液水合的药物的药理活性是反映 它们集中在气道表面上。很难测量人类受试者的气道药物浓度 使用传统方法。支气管镜灌注遭受可变稀释和不确定性的影响 采样，痰可能反映出主要来自大气道表面的异常分泌。 因此，我们将开发质谱方法，以准确测量药物的ASL浓度， 药物代谢产物和ASL稀释的标志物，可以将两者都应用于非侵入性气道样品，例如 呼气的呼吸冷凝物（EBC）以及从所有三个项目中获得的其他ASL样品。 2。药效学。量化粘纤毛功能对针对慢性的治疗的响应 阻塞性气道疾病需要对动物和动物的MCC/CC进行准确的，敏感的体内测量 人类模型。因此，我们将： 一个。通过跟踪荧光标记的珠子的气管速度来测量小鼠中的粘膜钙金清除率 对于基线和药物干预措施，与临床项目相似的药物干预措施。 b。使用标准化放射性示例的技术测量人类受试者的MCC/CC。两个都 基线MCC/CC和粘液溶剂治疗的影响将如项目111所述进行评估。 气道阻塞，睫状依赖的清除率（MCC），咳嗽依赖性清除（CC）和 描述清除异质性的新型终点将向项目调查人员提供。 c。工程师并产生具有控制尺寸和形状的新型颗粒，以在气道表面上沉积 1）准确跟踪肺部粘液的运动和2）允许多模式成像（例如 光子发射计算机断层扫描，正电子发射断层扫描[PET]或MRI），以更好地描绘 与患者肺部MCC异常的学位和部位与诊断成像结合 肺结构（CT和MRI）和炎症（PET）。