Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock

Abstract Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolo...

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Autores principales:	Michael A. Puskarich, Theodore S. Jennaro, Christopher E. Gillies, Charles R. Evans, Alla Karnovsky, Cora E. McHugh, Thomas L. Flott, Alan E. Jones, Kathleen A. Stringer, for the RACE Investigators
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/6ce1ffd631774c4e9df4a19cf077f90d
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spelling	oai:doaj.org-article:6ce1ffd631774c4e9df4a19cf077f90d2021-11-19T17:51:35ZPharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock1752-80621752-805410.1111/cts.13088https://doaj.org/article/6ce1ffd631774c4e9df4a19cf077f90d2021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13088https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90‐day mortality benefit from L‐carnitine. The independent predictive value of each pretreatment 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. Accounting 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 pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L‐carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90‐day sepsis mortality. Our proof‐of‐concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.Michael A. PuskarichTheodore S. JennaroChristopher E. GilliesCharles R. EvansAlla KarnovskyCora E. McHughThomas L. FlottAlan E. JonesKathleen A. Stringerfor the RACE InvestigatorsWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2288-2299 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Michael A. Puskarich Theodore S. Jennaro Christopher E. Gillies Charles R. Evans Alla Karnovsky Cora E. McHugh Thomas L. Flott Alan E. Jones Kathleen A. Stringer for the RACE Investigators Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
description	Abstract Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90‐day mortality benefit from L‐carnitine. The independent predictive value of each pretreatment 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. Accounting 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 pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L‐carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90‐day sepsis mortality. Our proof‐of‐concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.
format	article
author	Michael A. Puskarich Theodore S. Jennaro Christopher E. Gillies Charles R. Evans Alla Karnovsky Cora E. McHugh Thomas L. Flott Alan E. Jones Kathleen A. Stringer for the RACE Investigators
author_facet	Michael A. Puskarich Theodore S. Jennaro Christopher E. Gillies Charles R. Evans Alla Karnovsky Cora E. McHugh Thomas L. Flott Alan E. Jones Kathleen A. Stringer for the RACE Investigators
author_sort	Michael A. Puskarich
title	Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
title_short	Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
title_full	Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
title_fullStr	Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
title_full_unstemmed	Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock
title_sort	pharmacometabolomics identifies candidate predictor metabolites of an l‐carnitine treatment mortality benefit in septic shock
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/6ce1ffd631774c4e9df4a19cf077f90d
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Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock

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