title: Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock.
abstract: BACKGROUND
  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 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.
  
  
  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.
authors.affiliation: 1 Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Puskarich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Finkel
authors.forename: Alla
authors.initials: A
authors.lastname: Karnovsky
authors.forename: Alan E
authors.initials: AE
authors.lastname: Jones
authors.forename: Julie
authors.initials: J
authors.lastname: Trexel
authors.forename: Brooke N
authors.initials: BN
authors.lastname: Harris
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stringer
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000090:Acetoacetates / Q000097:blood; D000368:Aged; D002331:Carnitine / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D010641:Phenotype; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D014631:Valerates / Q000097:blood; D014803:Vitamin B Complex / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000090:Acetoacetates; D014631:Valerates; D014803:Vitamin B Complex; C004961:beta-hydroxyisovaleric acid; C016635:acetoacetic acid; D002331:Carnitine; D020155:3-Hydroxybutyric Acid
keywords: 3-hydroxybutyric acid; individualized medicine; ketone bodies; nuclear magnetic resonance; sepsis