Population Pharmacokinetics/Pharmacodynamics in Nonablative Stem Cell Recipients

描述（由申请人提供）： 非切除性造血干细胞移植（HCT）与无关供体移植物的数量大大增加了血液病和恶性肿瘤患者谁可以通过HCT治愈。然而，HCT方案的当前给药方法导致全身暴露量和相应的供体T细胞嵌合体百分比存在显著的患者间差异。母赠款有令人信服的数据表明，供体嵌合体百分比与非消融性HCT的疗效和毒性相关。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），沿着相关代谢产物，是供体嵌合体的生物标志物。为了检验这一假设，我们建议开发群体PK模型和有限的采样时间表，以表征个体患者的全身暴露，并使用每种药物活性的PD终点构建popPK-PD模型。我们提出了三个具体的目标进行测试，在患者接受氟达拉滨/全身照射条件，无关的外周血单核细胞移植，移植后免疫抑制的MMF和钙调磷酸酶抑制剂。在目的1中，我们将评价血浆氟达拉滨和细胞内氟达拉滨三磷酸盐（FTP）（其活性代谢产物）的PK和PD。使用一种新的分析方法，我们独特地准备测量从等待HCT的患者中获得的CD 4+和CD 8+细胞的体外FTP形成，并评估FTP形成的细胞机制。我们将评价氟达拉滨特异性PD，特别是评价这些PK终点与循环CD 4+和CD 8+细胞下降的关系。在目标2中，我们将描述MMF活性代谢产物麦考酚酸（MPA）的PK和PD特征，并证实我们的发现，即低MPA AUC会增加低百分比供体嵌合体和排斥反应的风险。我们还建议评估MPA清除的遗传机制，并表征MPA和肌苷一磷酸脱氢酶（IMPDH）活性的PD，MPA抑制的酶。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氟达拉滨和MMF的PK和药物特异性PD生物标志物相关。我们建议使用目的1和2中评价的PK和药物特异性PD标志物评价供体T细胞嵌合体的PD。我们的专业领域，结合我们的合作历史，证明我们已经准备好检验中心假设，从而为这些辅助研究提供了一个独特的机会，以改善接受HCT的血液病或恶性肿瘤患者的结局。这些研究的目的是确定与接受造血干细胞移植的患者中受体细胞和供体细胞之间的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如何立即响应-两种药物，氟达拉滨和霉酚酸酯。(End摘要）

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)