L-Carnitine Pharmacometabolomics in Sepsis (CaPS)

 描述（由申请人提供）：在败血症中使用L-肉碱进行早期干预是一种有前途的治疗策略，正在进行的临床试验RACE（sEpsis中快速给予肉碱）中进行测试。在本申请中，我们提出了L-肉毒碱败血症药物代谢组学（CaPS）研究，该研究提出L-肉毒碱也可用于“代谢挑战”试验，以代谢表型败血症的异质性。为了测试这一想法，我们将利用一个前所未有的和独特的机会，应用药物代谢组学领域来定义L-肉碱利用者和非利用者及其相关的代谢产物谱。这将通过使用从RACE可靠收集的血清样本来生成代谢组学数据，以确定代谢谱、临床表型、酰基肉毒碱水平和死亡率之间的相关关系来完成。我们的初步数据表明，药物代谢组学告知L-肉碱药物反应表型独立于序贯器官衰竭评估（SOFA）评分和乳酸水平。值得注意的是，我们还区分了L-肉碱补充剂的非利用者，他们的代谢紊乱更大，死亡率比L-肉碱利用者更高，这表明非利用者的代谢适应性受损。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，成功地实现了以下目标：1）比较L-卡尼汀治疗的脓毒症幸存者和非幸存者的治疗前差异和代谢紊乱随时间的变化;和2）确定L-肉碱利用和酰基肉碱水平之间的关系程度，作为线粒体代谢功能的测量。我们的总体假设是，L-肉碱的利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和强大的影响，因为它将促进药物代谢组学的应用，这是个性化医学的一个组成部分，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，我们希望：1）区分L-肉毒碱的代谢产物谱 与死亡率一致的利用者和非利用者;和2）肉毒碱利用与酰基肉毒碱相关的证据，酰基肉毒碱是线粒体功能的替代物。这些数据将支持L-肉毒碱“代谢挑战”试验的可行性，该试验将使败血症的及时代谢表型能够用于L-肉毒碱的III期研究中的入选标准。然而，从长远来看，这项工作超出了L-肉毒碱作为治疗剂的范围，因为：1）在肉毒碱利用中发现的代谢缺陷有望导致药物靶点机会的识别，推动药物发现和开发;和2）该测试将允许对患者进行分层以进行靶向代谢治疗。这项工作将为严重脓毒症的有效治疗提供精确的医学指导，推动知情的适应性临床试验设计的进步，并推进脓毒症代谢适应性的知识，这将推动药物发现。

 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.