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

Michael A. Puskarich, Michael A. Finkel, Alla Karnovsky, Alan E. Jones, Julie Trexel, Brooke N. Harris, Kathleen A. Stringer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 1H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of L-carnitine- and placebotreated 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.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalAnnals of the American Thoracic Society
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • 3-hydroxybutyric acid
  • Individualized medicine
  • Ketone bodies
  • Nuclear magnetic resonance
  • Sepsis

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