Population Pharmacokinetics/Pharmacodynamics in Nonablative Stem Cell Recipients

项目摘要 非消融性造血干细胞移植（HCT）与无关供体移植物已大大扩大 HCT可治愈的血液病和恶性肿瘤患者数量。 然而，HCT方案的当前给药方法导致全身免疫应答的显著患者间变异性。 暴露和相应百分比的供体T细胞嵌合体。父母赠款有令人信服的数据， 供体嵌合率与非消融性HCT的疗效和毒性相关。我们的中央 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）与相关代谢物沿着是供体嵌合的生物标志物。测试 基于这一假设，我们建议开发群体PK模型和有限采样时间表来表征 个体患者的全身暴露量，并使用每个特定的PD终点构建popPK-PD模型 药物的活性。我们提出了三个具体的目标，在接受氟达拉滨/全身的患者中进行测试 辐射预处理，无关的外周血单核细胞移植，和移植后 MMF和钙调磷酸酶抑制剂的免疫抑制。在目标1中，我们将评价血浆中的PK和PD 氟达拉滨和细胞内氟达拉滨三磷酸（FTP），其活性代谢物。使用一种新的分析 方法，我们是唯一准备测量体外FTP形成的CD 4+和CD 8+细胞获得自 等待HCT的患者，并评估FTP形成的细胞机制。我们会评估氟达拉滨- 特定PD，专门评价这些PK终点与循环CD 4+下降的关系 CD 8+细胞。在目标2中，我们将描述MMF活性代谢产物麦考酚酸的PK和PD特征 (MPA)，并证实我们的发现，即低MPA AUC会增加低百分比供体嵌合体的风险， 排斥反应我们还建议评估MPA清除的遗传机制，并描述 MPA和肌苷一磷酸脱氢酶（IMPDH）活性，该酶受MPA抑制。在目标3中， 我们建议评估供体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来评估供体T细胞嵌合体的PD 以及在目的1和2中评价的药物特异性PD标志物。我们的专业领域，结合 与我们的合作历史，证明我们已经准备好测试中心假设，因此， 为这些辅助研究提供了独特的机会，以改善血液病患者的结局。 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之间的平衡有关的特定因素， 接受造血干细胞移植的患者中的受体细胞和供体细胞。我们 我将研究两种类型的患者特异性因素：患者的身体如何分解， 他们的身体立即对两种药物产生反应，氟达拉滨和麦考酚酯。

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.