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: 7837473
• 负责人: Jeannine S McCune
• 金额: $ 29.39万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837473
• 关键词: Accounting; Acute Graft Versus Host Disease; Age; Allogenic; Ancillary Study; Area; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; Calcineurin inhibitor; Cell Transplantation; Cells; Chimerism; Collaborations; Data; Databases; Development; Donor Lymphocyte Infusion; Dose; Drug Kinetics; Equilibrium; Exposure to; Genetic; Goals; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immunosuppression; In Vitro; Individual; Inosine Monophosphate; Intervention; Intracellular Transport; Lead; Malignant - descriptor; Malignant Neoplasms; 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; Relapse; Research; Residual state; Resources; Risk; Role; Sampling; Schedule; Stem cell transplant; Stem cells; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Whole-Body Irradiation; analytical method; base; conditioning; enzyme activity; fludarabine; high risk; improved; meetings; mycophenolate mofetil; novel; parent grant; pharmacodynamic model; pharmacokinetic model; response; tripolyphosphate

PROJECT SUMMARY 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. PROJECT NARRATIVE 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.

项目摘要 具有无关供体移植物的非启动性造血干细胞移植（HCT）已大大扩展 可以治愈HCT的血液学疾病和恶性肿瘤的患者数量。 但是，当前的HCT方案给药方法导致全身性的大量室内变异性 暴露和相称的供体T细胞嵌合体。父母赠款具有令人信服的数据 供体嵌合体的百分比与非生殖器HCT的效率和毒性有关。我们的中心 假设是氟达拉滨的药代动力学（PK）和药物特异性药效学（PD） 霉酚酸酯（MMF）以及相关的代谢产物是供体嵌合体的生物标志物。测试 这个假设，我们建议开发人口PK模型和有限的抽样时间表以表征 单个患者的系统性暴露并使用针对每个特定的PD端点构建POPPK-PD模型 药物的活动。我们建议在接受氟达拉滨/总体的患者中测试三个特定目标 辐照调节，无关的外周血单核细胞移植物和后种植后 MMF和钙调神经蛋白抑制剂的免疫抑制。在AIM 1中，我们将评估血浆的PK和PD 氟达拉滨和细胞内氟达拉滨三磷酸（FTP），其活性代谢产物。使用新颖的分析 方法，我们被CD4+和CD8+细胞形成的视野中有毒。 等待HCT并评估FTP形成的细胞机制。我们将评估氟达拉滨 特定的PD，专门评估了这些PK终点的关系，而循环CD4+的下降 和CD8+细胞。在AIM 2中，我们将表征MMF活性代谢物，霉酚酸的PK和PD （MPA），并确认我们的发现，低MPA AUC会增加供体嵌合和供体百分比的风险 拒绝。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，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PK和药物特异性PD相关 氟达拉滨和MMF的生物标志物。我们建议用PK评估供体T细胞嵌合的PD 以及在目标1和2中评估的药物特异性PD标记。我们的各个专业领域结合 有了我们的合作历史，证明我们对我们进行了充分的努力来检验中心假设，因此 为这些辅助研究提供了独特的机会，以改善血液学患者的预后 接受HCT的疾病或恶性肿瘤。项目叙述 这些研究的目的是确定与患者的特定因素 接受造血干细胞移植的患者的受体细胞和供体细胞。我们 将考虑两种类型的患者特异性因素»患者的身体如何分解以及如何 他们的身体立即做出反应 - 两种药物，氟达拉滨和霉酚酸盐。