Improving Drug Development for the Critically Ill Child

描述（由申请人提供）：最近立法变化的影响集中在提高我们对治疗中使用的药物的认识！对儿童的影响正在慢慢实现，但目前的研究尚未调查疾病状态对药物处置的差异。这在危重儿童中尤为明显，他们的器官功能、全身水分、组织和血浆蛋白的变化都会影响治疗药物的配置和作用。本课题的长期研究目标是通过缩小我们对危重儿童常用药物的临床药理学知识的差距，优化危重儿童治疗药物的安全性和有效性。我们将使用复杂的药代动力学-药效学（PK-PD）建模技术和临床试验模拟来简化临床研究的开发和性能。我们的中心假设是，当利用表征良好的模型来解释药代动力学和药效学变化的来源时，信息丰富的临床试验可以更有效地设计。我们计划首先根据已发表的临床药理学数据构建选择模型，然后进行临床试验模拟，以设计危重儿童常用药物的前瞻性研究。根据我们的模型和试验模拟的结果，我们将继续进行两种常用药物（戊巴比妥和多巴胺）在危重儿童中的临床研究。最后，我们将把这些临床研究的结果整合到我们的模型中，以便在这一难以研究的儿科人群中进行更合理的药理学给药。对于这种有指导的培训，将采取两种相互补充的办法。第一部分将是正式的课程，涵盖临床药理学领域不可或缺的一系列主题。第二种方法将通过指导临床和实验室研究计划。这种密集的教学和指导培训将允许未来独立儿科临床调查员的发展。

DESCRIPTION (provided by applicant): The impact of recent legislative changes focused on improving our knowledge of drugs used in the treatment !of children is slowly being realized, but current studies have not investigated the differences in drug disposition afforded by disease state. This is most notable for critically ill children, in who changes in organ function, total body water, tissue and plasma proteins, can all affect the disposition and action of therapeutic drugs. The long-term research goal of this proposal is to optimize the safety and efficacy of drugs used in the treatment of critically ill children by bridging our gap in knowledge of the clinical pharmacology of drugs frequently used in these patients. We will use sophisticated pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques and clinical trial simulation to streamline the development and performance of clinical studies. Our central hypothesis is that informative clinical trials can be designed more efficiently when well characterized models that account for sources of variation in pharmacokinetics and pharmacodynamics are utilized. We plan to initially construct select models based on published clinical pharmacologic data, and then perform clinical trials simulations for the design of prospective studies of drugs frequently used in the care of critically ill children. Based on the results of our models and trial simulations, we will then carry forward and perform clinical studies of two frequently used drugs (pentobarbital and dopamine) in critically ill children. lastly, we will integrate results from these clinical studies back into our models to allow for pharmacologically more rational dosing in this difficult to study pediatric population. For this mentored training, two complementary approaches will be pursued. The first will be formal coursework covering a range of topics iintegral to the field of clinical pharmacology. The second approach will be through a mentored clinical and laboratory research program. This intensive didactic and mentored training will allow for the development of a future independent pediatric clinical investigator.