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.
Sepsis is a significant and growing human health concern. Unfortunately, we have very few effective therapies to treat sepsis and it is difficult to know which patients will favorably respond to any given treatment. This project entitled 'L-Carnitine Pharmacometabolomics in Sepsis' will introduce a personalized medicine approach called pharmacometabolomics to sepsis treatment. The information we acquire from this project is relevant to public health because it will help us determine which patients are more likely to respond to a new therapy, L-carnitine, will improve the design of future sepsis clinical trials and will aid in driving drug discovery for new sepsis therapeutics.
