PR000571 (Project)

Description:Rationale: Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. Objective: To utilize existing serum samples from the phase I clinical trial of L-carnitine treatment for severe sepsis to metabolically phenotype L-carnitine responders and non-responders. Methods: Serum samples collected prior to (T0) and after completion of the infusion (T24, T48) from patients randomized to either L-carnitine (12 g) or placebo for the treatment of vasopressor dependent septic shock were assayed by untargeted 1H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of L-carnitine and placebo treated patients at each time point were compared by ANOVA with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. Measurements and main results: 38 metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, 3-hydroxyisovalerate were different at T0 and over time in L-carnitine treated survivors versus non-survivors. Pathway analysis of pre-treatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating L-carnitine treatment response. Analysis of all patients based on pre-treatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153µM), patients were categorized as either high or low ketone. L-carnitine treated low ketone patients had greater utilization of carnitine as evidenced by lower post-treatment L-carnitine levels. The L-carnitine responders also had faster resolution of vasopressor requirement and a trend towards a greater improvement in mortality at 1 year (p = 0.038) compared with patients with higher 3-hydroxybutyrate. Conclusions: The results of this preliminary study, that were not readily apparent from the parent clinical trial, show a unique metabolite profile of L-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing L-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study. This study was published: Ann Am Thorac Soc 2015;12:46-56.