Population Pharmacokinetics/Pharmacodynamics in Nonablative Stem Cell Recipients

项目总结 非消融性造血干细胞移植(HCT)与非血缘关系的供者移植物的移植已经大大扩大 可以通过HCT治愈的血液病和恶性肿瘤患者的数量。 然而，目前HCT方案的给药方法导致患者之间的系统变异性很大。 暴露和相应百分比的供者T细胞嵌合体。父母的赠款有令人信服的数据 供者嵌合率与非消融性血细胞移植的疗效和毒性有关。我们的中央 假说是氟达拉滨和阿司匹林的药代动力学(PK)和药物特异性药效学(PD 霉酚酸酯(MMF)及其代谢产物是供体嵌合体的生物标志物。为了测试 在这一假设下，我们建议建立总体PK模型和有限抽样调度来刻画 单个患者的全身暴露情况，并使用特定于每个患者的PD端点构建PopPK-PD模型 毒品的活性。我们提出了在接受氟达拉滨/全身治疗的患者中进行测试的三个具体目标 辐射调理，一种无关的外周血单核细胞移植物，以及移植后 MMF和钙调神经磷酸酶抑制剂的免疫抑制。在目标1中，我们将评估血浆的PK和Pd 氟达拉滨及其活性代谢产物三磷酸氟达拉滨(Ftp)。使用一种新的分析方法 方法，我们独一无二地准备测量从以下来源获得的CD4和CD8细胞在体外形成FTP值 等待血细胞移植的患者，并评估FTP形成的细胞机制。我们将评估氟达拉滨- 特异性PD，特别是评估这些PK终点与循环中CD4下降的关系 和CD8细胞。在目标2中，我们将表征MMF的活性代谢物霉酚酸的PK和PD (Mpa)，并证实我们的发现，低Mpa AUC会增加低百分比供者嵌合体的风险，并 拒绝。我们还建议评估MPA清除的遗传机制，并描述PD的特征 甲孕酮和肌苷一磷酸脱氢酶(IMPDH)活性，该酶被甲孕酮抑制。在《目标3》中， 我们建议评估供者T细胞嵌合体百分比是否与PK和药物特异性PD相关 氟达拉滨和霉酚酸酯的生物标志物。我们建议用PK来评估供者T细胞嵌合体的PD 和药物特异性PD标志物在AIMS 1和2中进行评估。我们的各个专业领域，结合 通过我们的合作历史，证明我们已经做好了测试中心假设的准备，因此 为这些辅助研究改善血液病患者的预后提供了独特的机会 接受红细胞压积治疗的疾病或恶性肿瘤。项目叙事 这些研究的目标是确定与患者之间的平衡相关的特定于患者的因素 接受造血干细胞移植的患者的受者细胞和供者细胞。我们 我将研究两种类型的患者特定因素：患者的身体如何分解以及如何 他们的身体对两种药物--氟达拉滨和霉酚酸酯--立即有反应。

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.