Pharmacokinetics and modeling of betamethasone therapy in threatened preterm birth

 描述(由申请人提供)：该应用的目的和长期目标是通过个体化产前皮质类固醇治疗来优化母亲和新生儿的结局。围绕倍他米松(BMZ)，我们假设，通过更好地了解产前皮质类固醇的处置和作用，我们将能够开发出一种针对BMZ的个性化给药策略，这将改善新生儿的结局和安全性。本研究的目的是充分了解BMZ的配置、疗效和安全性，以改善其治疗用途，解决疗效差异。我们将通过两个具体目标来实现这一目标：1)我们将表征可能导致产前皮质类固醇改变新生儿结局的药代动力学和药物遗传变异；2)我们将开发一种新的个性化治疗模式，旨在减少差异和优化新生儿结局。已经建立了一个协作的多学科研究小组，具备完成这些研究所需的必要专门知识。为了实现这些目标，我们将利用我们成功的受试者招募基础设施，招募一批因预期早产而提出接受BMZ治疗的女性。这项研究将产生旨在最大化BMZ对新生儿益处的数据。然后，创建的个性化治疗模型可以在临床试验中进行验证和测试。这种个体化的治疗方法将对大量早产婴儿的治疗产生重大影响，这些婴儿可能没有得到目前剂量标准的充分治疗。这项建议具有创新性，因为它将是首批解决产前皮质类固醇结果差异的产科pharmacokinetic/pharmacodynamic/pharmacogenetic模拟研究之一，并将把遗传数据与药代动力学测量结合起来，以便更好地了解这些患者的药物反应。这项研究计划还具有巨大的潜力，可以作为一种模板，用于对各种怀孕条件进行更知情的个性化药物治疗研究。

 DESCRIPTION (provided by applicant): The purpose and long-term goal of this application is to optimize maternal and neonatal outcomes by individualizing antenatal corticosteroid therapy. Focusing on betamethasone (BMZ), we hypothesize that by better understanding the disposition and action of antenatal corticosteroids, we will be able to develop an individualized dosing strategy for BMZ that will improve neonatal outcomes and safety. The objective of this study is to fully interrogate the disposition, efficacy, and safety of BMZ to improve its therapeutic use an resolve efficacy discrepancies. We will accomplish this through two specific aims: 1) We will characterize the pharmacokinetics and the pharmacogenetic variations that may lead to altered neonatal outcomes in response to antenatal corticosteroids; and 2) We will develop a novel personalized therapeutic model aimed at reducing disparities and optimizing neonatal outcomes. A collaborative multidisciplinary research team with the necessary expertise required to complete these studies is in place. To accomplish these aims we will utilize our successful subject recruitment infrastructure to recruit a cohort of women presenting for BMZ therapy due to anticipated preterm birth. The research will generate data aimed at maximizing the neonatal benefits from BMZ. The individualized therapeutic model created then can be validated and tested in a clinical trial. This individualized approach to treatment would have a significant impact on the therapy of a large number of babies born prematurely who may be inadequately treated by the current dosing standard. The proposal is innovative in that it would be one of the first obstetric pharmacokinetic/pharmacodynamic/pharmacogenetic modeling studies to address outcome disparities from antenatal corticosteroids and would combine the genetic data with pharmacokinetic measurements to allow better understanding of the drug response in these patients. This program of research also has great potential to serve as a template for more informed individualized pharmacotherapy investigations for a wide range of pregnancy conditions.