ERYTHROPOEITIN PHYSIOLOGY AND PHARMACOLOGY IN INFANTS

婴儿促红细胞生成素的生理学和药理学

• 批准号: 6110098
• 负责人: JOHN Andrew WIDNESS
• 金额: $ 36.97万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110098
• 关键词: anemia; biotin; blood /lymphatic pharmacology; blood disorder chemotherapy; clinical research; erythropoietin; hemodynamics; human subject; infant animal; iron metabolism; nonhuman therapy evaluation; pharmacokinetics; premature infant human; radiotracer; recombinant proteins; sheep

The many red blood cells (RBC) transfusions administered to preterm infants as treatment for anemia are expensive and pace them at risk for blood-borne infections and other transfusion related complications. The long-term objectives of Project #1 is to develop effective strategies for optimally administering recombinant human erythropoietin (r-HuEPO) in the treatment of anemia of prematurity. Achieving this goal is important and timely because r-HuEPO remains an evolving clinical therapy without a clear consensus of how, when and for whom it should be used in these patients. Our objective will be accomplished by performed mechanistically based EPO pharmacokinetic (PK) and pharmacodynamic (PD) studies in sheep and human subjects using sensitive and accurate tracer methodologies. Achieving maximal stimulation for erythropoiesis relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and its complex PK and PD behaviors. Because plasma EPO concentrations in anemic preterm infants are reduced relative to those in anemic adults, inadequate EPO production has been suggested as a primary underlying mechanism for the anemia these neonates inevitably develop and as justification for r-HuEPO treatment. Based on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary mechanism, but that other mechanisms may be more important. The basis for this speculation is an expanding body of data indicating that EPO's in vivo disposition occurs primarily via a saturable, receptor-mediated process. As an overall hypothesis we speculate that EPO's in vivo PK and PD are determined by the number and affinity of EPO receptors (EPO-R's) located predominantly on the body's expandable pool of erythroid progenitor cells. This hypothesis is consistent with the observation that EPO's PK behavior is non-linear, that EPO elimination is 3 to 4 times greater in premature infants than adults, and that the red marrow occupies a 3- to 4-fold greater volume per kg body weight in young children than adults. Because of their sensitivity and accuracy, PK methodologies utilizing labeled EPO tracers are ideally suited for investigating EPO's non-linear behavior and for directly measuring its endogenous production rate. In addressing our proposal's three aims, 125I-r-HuEPO and biotinylated r- HuEPO and biotinylated r-HuEPO (Bio-EPO) will be administered as tracers in advanced system analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for biotinylating r-HuEPO retaining its PK behavior and for measuring Bio-EPo in tracer amounts will be developed and validated. In Aims #2 and #3, 125I-r-HuEPO tracer methodology will first be applied in vivo experiments in sheep to determine the effect of perturbations in erythropoiesis (i.e., by bone marrow ablation and by phlebotomy-induced anemia and r-HuEPO treatment) on EPO's PK, PD, and production rate. When Bio-EP becomes available as a tracer, similar studies will be conducted in human infant and adult study groups. Knowledge gained about EPO's PK and PD will permit more optimal use of r-HuEPO thus leading to a reduction in the multiple RBC transfusions typically recovered by preterm infants.

对早产的许多红细胞（RBC）输血 婴儿作为贫血的治疗很昂贵，并加快他们的风险 血传播感染和其他与输血有关的并发症。这 项目＃1的长期目标是制定有效的策略 用于最佳管理重组人红细胞生物素（R-Huepo） 在治疗早产的贫血中。实现这一目标是 重要和及时，因为R-Huepo仍然是不断发展的临床 没有明确共识如何，何时以及应为谁的治疗 用于这些患者。我们的目标将通过执行来实现 基于机械的EPO药代动力学（PK）和药效学（PD） 使用敏感且准确的示踪剂研究绵羊和人类受试者 方法论。实现红细胞生成的最大刺激依赖 在某种程度上，迄今为止对EPO的全面理解 难以捉摸的体内代谢，部分依赖于开发 对迄今为止难以捉摸的体内代谢的全面了解 及其复杂的PK和PD行为。因为血浆EPO浓度 在贫血的早产中相对于贫血的婴儿减少了 成人，已建议将EPO的生产作为主要生产 贫血的基本机制这些新生儿不可避免地会发展 并作为R-Huepo治疗的理由。基于直接动物和 间接人类数据，我们建议EPO的生产不足不是 关于直接动物和间接人类数据的主要数据，我们建议 EPO生产不足不是主要机制，而是其他机制 机制可能更重要。 这个猜测的基础是 扩大数据体，表明EPO的体内处置发生 主要通过可饱和的受体介导的过程。总体而言 假设我们推测EPO的体内PK和PD由 EPO受体（EPO-R）的数量和亲和力主要位于 在人体可扩展的红细胞祖细胞中。这 假设与观察到EPO的PK行为是一致的 非线性，EPO消除的早产是3至4倍 婴儿比成人，红骨髓占3至4倍 年幼的儿童每公斤体重的体积大于成人。因为 PK方法学的灵敏度和准确性利用了标签 EPO示踪剂非常适合研究EPO的非线性 行为并直接测量其内源性生产率。在 解决我们的提案的三个目标，即125i-r-Huepo和生物素化的R- Huepo和生物素化的R-Huepo（Bio-Epo）将作为示踪剂管理 在基于系统分析的高级PK和PD研究中 和人类。在AIM＃1中，基于分析的PK和 PD研究分别在绵羊和人类中进行。在AIM＃1中 生物素化R-Huepo的方法保留其PK行为和 将开发和验证示踪剂量中的生物EPO。在 目标＃2和＃3，125i-r-Huepo示踪方法将首先应用于 绵羊的体内实验，以确定扰动的影响 红细胞生成（即，通过骨髓消融和通过静脉切开术诱导的 关于EPO的PK，PD和生产率的贫血和R-Huepo治疗）。什么时候 Bio-EP作为示踪剂可用，将进行类似的研究 在人类婴儿和成人研究小组中。关于EPO的PK的知识 PD将允许更多最佳使用R-Huepo，从而导致A 通常减少多个RBC输血的降低 早产婴儿。