Population Pharmacokinetics/Pharmacodynamics in Nonablative Stem Cell Recipients

非剥脱干细胞受体的群体药代动力学/药效学

• 批准号: 7996579
• 负责人: Jeannine S McCune
• 金额: $ 42.72万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996579
• 关键词: Accounting; Acute Graft Versus Host Disease; Age; Allogenic; Ancillary Study; Area; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; CSF3 gene; Calcineurin inhibitor; Cell Transplantation; Cells; Chimerism; Collaborations; Data; Databases; Development; Donor Lymphocyte Infusion; Dose; Drug Kinetics; Equilibrium; Exposure to; Genetic; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immunosuppression; In Vitro; Individual; Inosine Monophosphate; Intervention; Intracellular Transport; Lead; Malignant - descriptor; Measures; Methods; Modeling; Mycophenolate; Mycophenolic Acid; National Heart, Lung, and Blood Institute; Non-Malignant; Outcome; Oxidoreductase; Parents; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Population; Procedures; Prodrugs; Recording of previous events; Regimen; Relapse; Research; Residual state; Resources; Risk; Role; Sampling; Schedule; Stem cell transplant; Stem cells; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Whole-Body Irradiation; abstracting; analytical method; base; conditioning; enzyme activity; fludarabine; high risk; improved; meetings; mycophenolate mofetil; novel; parent grant; pharmacodynamic model; pharmacokinetic model; response; tripolyphosphate

DESCRIPTION (provided by applicant): Nonablative hematopoietic stem cell transplantation (HCT) with an unrelated donor graft has greatly expanded the number of patients suffering from hematologic diseases and malignancies who can be cured by HCT. However, current dosing methods for HCT regimens lead to substantial interpatient variability in the systemic exposure and commensurate percent donor T-cell chimerism. The parent grants have compelling data that percent donor chimerism is associated with the efficacy and toxicity of nonablative HCT. Our central hypothesis is the pharmacokinetic (PK) and drug-specific pharmacodynamics (PD) of fludarabine and mycophenolate mofetil (MMF), along with relevant metabolites, are biomarkers for donor chimerism. To test this hypothesis, we propose to develop population PK models and limited sampling schedules to characterize an individual patient's systemic exposure and to build popPK-PD models using PD endpoints specific for each drug's activity. We propose three specific aims to be tested in patients receiving fludarabine/total body irradiation conditioning, an unrelated peripheral blood mononuclear cell graft, and postgrafting immunosuppression of MMF and a calcineurin inhibitor. In Aim 1, we will evaluate the PK and PD of plasma fludarabine and intracellular fludarabine triphosphate (FTP), its active metabolite. Using a novel analytical method, we are uniquely poised to measure in-vitro FTP formation by CD4+ and CD8+ cells obtained from patients awaiting HCT and evaluate the cellular mechanisms of FTP formation. We will evaluate fludarabine- specific PD, specifically evaluating the relationship of these PK endpoints with the decline in circulating CD4+ and CD8+ cells. In Aim 2, we will characterize the PK and PD of MMF's active metabolite, mycophenolic acid (MPA), and to confirm our findings that a low MPA AUC increases the risk of low percent donor chimerism and rejection. We also propose to evaluate the genetic mechanisms of MPA clearance and to characterize the PD of MPA and inosine monophosphate dehydrogenase (IMPDH) activity, the enzyme inhibited by MPA. In Aim 3, we propose to evaluate if percent donor T-cell chimerism is associated with the PK and drug-specific PD biomarkers of fludarabine and MMF. We propose to evaluate the PD of donor T-cell chimerism with the PK and drug-specific PD markers evaluated in Aims 1 and 2. Our individual areas of expertise, in combination with our history of collaborations, demonstrate that we are well-poised to test the central hypothesis, thus providing a unique opportunity for these ancillary studies to improve outcomes for patients with hematologic disease or malignancies receiving HCT. The goal of these studies is to identify patient-specific factors related to the balance between the recipient cells and donor cells in patients who receive a hematopoietic stem cell transplant. We will look at two types of patient-specific factors - how the patients' body breaks down and how their bodies immediately responds - to two drugs, fludarabine and mycophenolate. (End of Abstract)

描述（由申请人提供）： 具有无关供体移植物的非启动性造血干细胞移植（HCT）大大扩大了可以通过HCT治愈的血液学疾病和恶性肿瘤患者的数量。但是，当前的HCT方案给药方法导致全身暴露和相称的供体T细胞嵌合体的大量室内变异性。父母的赠款具有令人信服的数据，即供体嵌合的百分比与非启动性HCT的功效和毒性有关。我们的中心假设是氟达拉滨和霉酚酸酯（MMF）的药代动力学（PK）和药物特异性药效学（PD），以及相关代谢物，是供体嵌合体的生物标志物。为了检验这一假设，我们建议开发人口PK模型和有限的采样时间表，以表征单个患者的系统性暴露，并使用针对每种药物活动的PD端点构建POPPK-PD模型。我们提出要在接受氟达拉滨/全身辐照调节的患者中测试三个特定目标，无关的外周血单核细胞移植物以及MMF和钙调神经蛋白抑制剂的免疫抑制后进行的。在AIM 1中，我们将评估血浆氟达滨和细胞内氟达拉滨三磷酸（FTP）的PK和PD，即其活性代谢物。使用一种新颖的分析方法，我们唯一准备通过从等待HCT的患者获得的CD4+和CD8+细胞来测量体外FTP形成，并评估FTP形成的细胞机制。我们将评估氟达拉滨特异性PD，特别评估这些PK终点与循环CD4+和CD8+细胞下降的关系。在AIM 2中，我们将表征MMF活性代谢产物，霉酚酸（MPA）的PK和PD，并确认我们的发现，低MPA AUC会增加供体嵌合和排斥的较低百分比的风险。我们还建议评估MPA清除率的遗传机制，并表征MPA和肌苷一磷酸脱氢酶（IMPDH）活性的PD，即MPA抑制的酶。在AIM 3中，我们建议评估供体T细胞嵌合的百分比是否与Fludarabine和MMF的PK和药物特异性PD生物标志物有关。我们建议评估AIM 1和2中评估的PK和药物特异性PD标记的供体T细胞嵌合体的PD。我们的专业知识领域以及我们的协作史结合了我们的合作历史，表明我们已经很好地测试了中心假设，从而为这些偏爱的疾病提供了止血病患者的独特机会。这些研究的目的是确定接受造血干细胞移植的患者中与受体细胞和供体细胞之间平衡相关的患者特异性因素。我们将研究两种类型的患者特异性因素 - 患者的身体如何分解以及他们的身体立即反应 - 两种药物：氟达拉滨和霉酚酸盐。 （抽象的结尾）