Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock

AbstractBackgroundSepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent study demonstrated a non-significant reduction in mortality.MethodsA pharmacometabolomics study of patients (n=250) in a Phase II trial of L-carnitine to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine. The independent predictive value of each pre-treatment metabolite concentration, adjusted for L-carnitine dose, on 90-day mortality was determined by logistic regression. A grid-search analysis maximizing the Z-statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L-carnitine responsive patients. Threshold concentrations were further assessed by hazard-ratio and Kaplan-Meier estimate.FindingsAccounting for L-carnitine treatment and dose, 11 1H-NMR metabolites and 12 acylcarnitines were independent predictors of 90-day mortality. Based on the grid-search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L-carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with acetylcarnitine ≥35µM were less likely to die at 90 days if treated with L-carnitine (18 g) versus placebo (p=0.01 by log rank test).InterpretationMetabolomics identified independent predictors of 90-day sepsis mortality. Our proof-of-concept approach shows how pharmacometabolomics may be useful for tackling the heterogeneity of sepsis and informing clinical trial design. Also, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, since sepsis induces alterations in numerous metabolite concentrations.