Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock.

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TitlePharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock.
Publication TypeJournal Article
Year of Publication2015
AuthorsPuskarich MA, Finkel MA, Karnovsky A, Jones AE, Trexel J, Harris BN, Stringer KA
JournalAnn Am Thorac Soc
Volume12
Issue1
Pagination46-56
Date Published2015 Jan
ISSN2325-6621
Abstract

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.OBJECTIVES: To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l-carnitine responders and nonresponders.METHODS: Serum samples collected before (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 (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks.MEASUREMENTS AND MAIN RESULTS: Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment 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 pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 μM), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use 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 toward 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, which 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.

DOI10.1513/AnnalsATS.201409-415OC
Alternate JournalAnn Am Thorac Soc
PubMed ID25496487
PubMed Central IDPMC4342803
Grant ListDK097153 / DK / NIDDK NIH HHS / United States
R01 GM103799 / GM / NIGMS NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States