L-Carnitine Pharmacometabolomics in Sepsis (CaPS)

 描述(申请人提供)：脓毒症早期应用L-卡尼汀是一种很有前景的治疗策略，正在进行的临床试验RACE(快速给药)中正在进行测试。在这一应用中，我们提出了脓毒症的L-卡尼汀药物代谢组学(CAPS)研究，认为L-卡尼汀也可以作为一种代谢挑战试验来对脓毒症的异质性进行代谢表型。为了验证这一想法，我们将利用一个前所未有的独特机会，应用药物代谢学领域来定义L-卡尼汀的使用者和非使用者及其相关的代谢物图谱。这将通过使用从RACE收集的可靠的血清样本来生成代谢组学数据来完成，以确定代谢概况、临床表型、酰肉碱水平和死亡率之间的相关关系。我们的初步数据显示，药物代谢组学独立于序贯器官衰竭评估(SOFA)评分和乳酸水平而影响L-卡尼汀的药物反应表型。值得注意的是，我们还区分了不服用L肉碱补充剂的人，他们的代谢紊乱程度比L肉碱补充者更严重，死亡率有升高的趋势，这表明不服用L肉碱的人代谢适应性受损。凭借在代谢组学方面的良好记录和一支高素质的研究团队，我们已做好充分准备，以成功实现拟议的目标：1)比较L卡尼汀治疗脓毒症幸存者和死亡患者治疗前的差异和代谢紊乱随时间的变化；2)确定L卡尼汀的利用与酰卡尼汀水平之间的关系程度，以衡量线粒体代谢功能。我们的主要假设是，L-卡尼汀的使用程度与严重脓毒症患者的代谢适应性和死亡率直接相关。总的来说，这项工作将对该领域产生持续而强大的影响，因为它将推进药物代谢组学的应用，药物代谢组学是个性化药物在脓毒症药物治疗中的一个组成部分，独立于RACE研究，这将推动脓毒症治疗的范式转变，因为在研究完成时，我们预计将有：1)区分L-卡尼汀的代谢物 与死亡率一致的使用者和非使用者；2)证据表明，肉碱的利用与酰基肉碱有关，后者是线粒体功能的替代品。这些数据将支持L-卡尼汀“代谢挑战”测试的可行性，该测试将能够及时对脓毒症进行代谢表型分型，并可用作L-卡尼汀III期研究的纳入标准。然而，从长远来看，这项工作超出了L-卡尼汀的治疗范围，因为：1)肉碱利用中发现的代谢缺陷有望导致识别药物靶向机会，从而推动药物的发现和开发；2)该测试将允许患者分层接受靶向代谢治疗。这项工作将为有效治疗严重脓毒症提供精确的医学指导，推动知情适应性临床试验设计的进步，并促进对脓毒症代谢适应性的认识，从而推动药物开发。

 DESCRIPTION (provided by applicant): Early intervention with L-carnitine in sepsis is a promising therapeutic strategy that is being tested in the ongoing clinical trial, RACE (Rapid Administration of Carnitine in sEpsis). In this application, we propose the L-Carnitine Pharmacometabolomics in Sepsis (CaPS) study that proposes that L-carnitine can also be used a "metabolic challenge" test to metabolically phenotype the heterogeneity of sepsis. To test this idea, we will exploit an unprecedented and unique opportunity to apply the field of pharmacometabolomics to define L-carnitine utilizers and non-utilizers and their associated metabolite profiles. This will be done by using reliably collected serum samples from RACE to generate metabolomics data to identify correlational relationships between metabolic profiles, clinical phenotypes, acyl-carnitine levels and mortality. Our preliminary data show that pharmacometabolomics informs L-carnitine drug response phenotypes independent of Sequential Organ Failure Assessment (SOFA) scores and lactate levels. Notably, we also differentiated non-utilizers of L-carnitine supplementation who had a greater derangement in metabolism and a trend towards higher mortality than L-carnitine utilizers, suggesting non-utilizers have impaired metabolic adaptiveness. With a demonstrated track-record in metabolomics and a highly qualified investigative team, we are well prepared to successfully accomplish the proposed aims which are to: 1) Compare the pre-treatment differences and changes over time in metabolic derangements in L-carnitine-treated sepsis survivors and non-survivors; and 2) Determine the extent of the relationship between L-carnitine utilization and levels of acylcarnitines as a measurement of mitochondrial metabolic function. Our overarching hypothesis is that the extent of L-carnitine utilization is directly linked to metabolic adaptivenes and mortality in patients with severe sepsis. Collectively, this work will exert a sustained and powerful influence on the field because it will advance the application of pharmacometabolomics, a component of personalized medicine to sepsis pharmacotherapy, independent of the RACE study, that will drive a paradigm shift in sepsis therapeutics because at the study's completion, we expect to have: 1) differentiating metabolite profiles of L-carnitine utilizers and non-utilizers that coincide with mortality; and 2) evidence that carnitine utilizatio is associated with acyl-carnitines, a surrogate of mitochondrial function. These data will support the feasibility of an L- carnitine "metabolic challenge" test that will enable timely metabolic phenotyping of sepsis that can be used for inclusion criteria in the phase III study of L-carnitine However, in the long-term, this work goes beyond the scope of L-carnitine as a therapeutic because: 1) the found metabolic defects in carnitine utilization are expected to result in the identification of drug target opportunities, driving drug discovery and development; and 2) the test will permit the stratification of patients to targeted metabolic therapy. This work will provie a precision medicine directive for the effective treatment of severe sepsis, fuel the advancement of well-informed adaptive clinical trial design, and advance knowledge of metabolic adaptiveness in sepsis that will drive drug discovery.