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

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.

• Authors: Michael A Puskarich, Michael A Finkel, Alla Karnovsky, Alan E Jones, Julie Trexel, Brooke N Harris, Kathleen A Stringer
• Journal: Annals of the American Thoracic Society (Ann Am Thorac Soc) Vol. 12 Issue 1 Pg. 46-56 (Jan 2015) ISSN: 2325-6621 [Electronic] United States
• PMID: 25496487 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetoacetates
• Valerates
• Vitamin B Complex
• beta-hydroxyisovaleric acid
• acetoacetic acid
• Carnitine
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid (blood)
• Acetoacetates (blood)
• Aged
• Carnitine (pharmacokinetics)
• Female
• Humans
• Magnetic Resonance Spectroscopy
• Male
• Metabolomics (methods)
• Middle Aged
• Phenotype
• Shock, Septic (drug therapy, metabolism)
• Treatment Outcome
• Valerates (blood)
• Vitamin B Complex (pharmacokinetics, therapeutic use)