Optimizing GVHD Prevention with Systems Pharmacology Models

利用系统药理学模型优化 GVHD 预防

• 批准号: 9757625
• 负责人: Jeannine S McCune
• 金额: $ 61.95万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757625
• 关键词: Acute Graft Versus Host Disease; Age; Allogenic; Area; Cells; Characteristics; Cities; Clinical Data; Complex; Computer Simulation; Cyclophosphamide; Data; Disease; Disease Pathway; Disease Progression; Dose; Drug Kinetics; Engraftment; Enrollment; Enzymes; Equilibrium; FOXP3 gene; Goals; Graft-Versus-Tumor Induction; Human; Hybrids; IL2RA gene; Immune response; Immunosuppressive Agents; In Vitro; Individual; Inosine Monophosphate; Knowledge; Link; Malignant Neoplasms; Metabolic; Metabolic Pathway; Modeling; Mycophenolic Acid; National Cancer Institute; Nature; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Plasma; Population; Process; Prodrugs; Prospective cohort; Publishing; Regimen; Regulatory T-Lymphocyte; Retrospective cohort; Sampling; Schedule; Severity of illness; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Tacrolimus; Testing; Time; Translations; Transplant Recipients; Weight; base; biological systems; cohort; cytotoxic; disorder control; disorder prevention; experience; experimental study; graft vs host disease; hematopoietic cell transplantation; high risk; immunoreaction; improved; mathematical model; model building; mortality; mycophenolate mofetil; novel; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; population based; post-transplant; pre-clinical; prospective; standard of care; study population; success

PROJECT SUMMARY Quantitative systems pharmacology (QSP) is a rapidly expanding area that integrates available in vitro, preclinical, and clinical data representing existing knowledge to achieve a reverse translation. Reverse translation uses real-time human clinical data to directly inform new discoveries, of existing therapies and attributes of disease progression. Here, we seek to be the first to build a QSP model to, a priori, predict interpatient pharmacokinetics and pharmacodynamics using population priors (population pharmacokinetic or popPK modeling) and physiologic predictions (using physiologically based pharmacokinetic or PBPK modeling) combined with pharmacodynamic models based on in vitro and preclinical data. We will apply this novel hybrid popPK-PBPK-PD QSP model to allogeneic hematopoietic cell transplant (HCT) because its success requires a delicate balance as the grafting of cells from one individual (donor) to another (host, the HCT recipient). Guided by our preliminary data, our working hypothesis is that QSP modeling can minimize interindividual variability of these immunosuppressants, while also optimizing the novel graft versus host disease (GVHD) regimen of post- transplant cyclophosphamide (PTCy). Aim 1 seeks to identify the optimal PTCy dose using popPK and PBPK models. Our preclinical data shows that PTCy has a narrow dose window, with intermediate doses having the lowest GVHD rates. To achieve the optimal PTCy dose in each patient, we seek to develop a validate a popPK- PBPK model building upon our unique expertise in quantitating 4-hydroxycyclophosphamide (4HCY), the primary precursor to the cytotoxic metabolite of CY and personalizing CY using popPK-guided dosing. This hybrid popPK-PBPK CY model will be developed using our retrospective and prospective (n=150) cohort. The prospective cohort will be enrolled at National Cancer Institute (NCI) and City of Hope (COH). The NCI cohort will determine if the PTCy dose and schedule can be reduced (by 75%) without compromising GVHD rates; the COH cohort will use the traditional PTCy dosing. In Aim 2, we will characterize the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA), the active metabolite of MMF, with its target enzyme inosine monophosphate dehydrogenase (IMPDH). Like CY, MPA has substantive pharmacokinetic variability but different metabolic and transport pathways so separate pharmacokinetic models are needed. We seek to create a popPK-PBPK-PD model to identify the optimal plasma exposure of MPA and IMPDH activity. In Aim 3, we will create a quantitative systems pharmacology (QSP) model of T-cell response and acute GVHD. Our preclinical data show that acute GVHD prevention with PTCy is associated with reduction of CD4+CD25-Foxp3- conventional T-cell (Tcon) proliferation at day +7 followed by the preferential expansion of CD4+CD25+Foxp3+ regulatory T cells (Tregs) at day +21. Building upon fully-integrated immune response model (FIRM), we seek integrate in vitro, preclinical, and clinical data to build a QSP model.

项目摘要 定量系统药理学（QSP）是一个快速扩展的区域，可在体外可用， 临床前和代表现有知识的临床数据以实现反向翻译。撤销 翻译使用实时人类临床数据直接告知新发现，现有疗法和 疾病进展的属性。在这里，我们试图成为第一个建立QSP模型的人，即先验地预测 使用种群先验的药物室内药代动力学和药效学（种群药代动力学或 POPPK建模）和生理预测（使用基于生理的药代动力学或PBPK建模） 与基于体外和临床前数据的药效学模型结合使用。我们将应用这种新颖的混合动力车 POPPK-PBPK-PD QSP模型到同种异体造血细胞移植（HCT），因为其成功需要 微妙的平衡是从一个个体（供体）到另一个单个（宿主，HCT接受者）的嫁接。指导 通过我们的初步数据，我们的工作假设是QSP建模可以最大程度地减少个体间个体可变性 这些免疫抑制剂，同时还优化了新的移植物与宿主疾病（GVHD）的治疗方案 移植环磷酰胺（PTCY）。 AIM 1寻求使用POPPK和PBPK识别最佳PTCY剂量 型号。我们的临床前数据表明，PTCY具有狭窄的剂量窗口，中间剂量具有 最低GVHD率。为了达到每位患者的最佳PTCY剂量，我们寻求开发验证poppk- PBPK模型基于我们在定量4-羟基环磷酰胺（4HCY）的独特专业知识的基础上， 使用POPPK引导的剂量的CY和个性化CY的细胞毒性代谢产物的主要前体。这 混合POPPK-PBPK CY模型将使用我们的回顾性和前瞻性（n = 150）队列开发。这 潜在的队列将入学到国家癌症研究所（NCI）和希望之城（COH）。 NCI队列 将在不损害GVHD率的情况下确定PTCY剂量和时间表是否可以降低（75％）；这 COH队列将使用传统的PTCY剂量。在AIM 2中，我们将描述药代动力学和 MMF的活性代谢物的霉酚酸（MPA）的药效学及其靶酶肌苷 单磷酸脱氢酶（IMPDH）。像CY一样，MPA具有实质性的药代动力学变异性，但 需要不同的代谢和运输途径，因此需要单独的药代动力学模型。我们试图创造 POPPK-PBPK-PD模型，以识别MPA和IMPDH活性的最佳血浆暴露。在AIM 3中，我们将 创建T细胞响应和急性GVHD的定量系统药理学（QSP）模型。我们的临床前 数据表明，PTCY的急性GVHD预防与CD4+CD25-Foxp3-的减少有关 第+7天的常规T细胞（TCON）增殖，然后优先扩展CD4+CD25+FOXP3+ 调节性T细胞（Tregs）在+21天。在完全综合的免疫反应模型（公司）的基础上，我们寻求 整合体外，临床前和临床数据以构建QSP模型。