Pharmacometabolomics of L-Carnitine Treatment Response Phenotypes in Patients with Septic Shock
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Sepsis
PROVIDER: ST000785 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| mwtab | Other |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description: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.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.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.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 ?M), 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.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.
| S-EPMC4342803 | biostudies-literature
Project description: Not available
| ST001319 | MetabolomicsWorkbench
Project description: Not available
| ST001354 | MetabolomicsWorkbench
Project description: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 1 H-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.
| S-EPMC8604225 | biostudies-literature
Project description: Not available
| S-EPMC7790338 | biostudies-literature
Project description:IntroductionSepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine that supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences.MethodsTo further understand the association between L-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1-year survivors and nonsurvivors within treatment groups.ResultsMortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. L-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm.ConclusionsIn human patients with septic shock, L-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to L-carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment.
| S-EPMC5847421 | biostudies-literature
Project description:Study objectiveLevocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock.DesignPopulation PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates.Data sourceWe leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation.Patients and interventionPatients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo.Measurements and main resultsThe final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race.ConclusionsHigh-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.
| S-EPMC10841498 | biostudies-literature
Project description:BackgroundSepsis is characterized by metabolic disturbances, and previous data suggest a relative carnitine deficiency may contribute to metabolic dysfunction. Studies regarding safety and patient-centered efficacy of carnitine during septic shock are lacking.MethodsThis was a double-blind randomized control trial of levocarnitine (L-carnitine) infusion vs normal saline for the treatment of vasopressor-dependent septic shock. Patients meeting consensus definition for septic shock with a cumulative vasopressor index ≥ 3 and sequential organ failure assessment (SOFA) score ≥ 5 enrolled within 16 hours of the recognition of septic shock were eligible. The primary safety outcome was difference in serious adverse events (SAEs) per patient between groups. Efficacy outcomes included proportion of patients demonstrating a decrease in SOFA score of 2 or more points at 24 hours and short- and long-term survival.ResultsOf the 31 patients enrolled, 16 were in the L-carnitine and 15 were in the placebo arm. There was no difference in SAEs between placebo and intervention (2.1 vs 1.8 SAEs per patient, P = .44). There was no difference in the proportion of patients achieving a decrease in SOFA score of 2 or more points at 24 hours between placebo and treatment (53% vs 44%, P = .59). Mortality was significantly lower at 28 days in the L-carnitine group (4/16 vs 9/15, P = .048), with a nonsignificant improved survival at 1 year (P = .06).ConclusionL-carnitine infusion appears safe in vasopressor-dependent septic shock. Preliminary efficacy data suggest potential benefit of L-carnitine treatment, and further testing is indicated.
| S-EPMC4069250 | biostudies-literature
Project description:PurposeImproved understanding of characteristics that may influence treatment response across phenotypes may help guide treatment decisions.Patients and methodsThis was a post hoc analysis of MENSA, a multicenter, randomized, double-blind, placebo-controlled trial (NCT01691521). Patients aged ≥12 years with severe eosinophilic asthma received mepolizumab (75 mg intravenously or 100 mg subcutaneously) or placebo, plus standard of care, every 4 weeks for 32 weeks. Outcomes assessed were the annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire (ACQ)-5 score. Subgroup analyses were performed by baseline blood eosinophil count (<150, ≥150-300, ≥300 cells/μL) within atopic subgroups (non-atopic [specific immunoglobulin E <0.35 kU/L], atopic [≥0.35-17.5 kU/L], strongly atopic [>17.5 kU/L]), and by house dust mite (HDM) sensitivity.ResultsOf 576 patients analyzed, 272 were non-atopic, 181 were atopic and 94 were strongly atopic; 29 had missing atopy data. In patients with blood eosinophil counts ≥300 cells/µL, mepolizumab versus placebo reduced clinically significant exacerbations by 74%, 43% and 25% in the non-atopic, atopic and strongly atopic subgroups. Similar reductions were observed in all atopic subgroups in other blood eosinophil count categories where there were sufficient patient numbers for analysis, except for non-atopic patients with baseline blood eosinophil counts of <150 cells/μL. Improvements in ACQ-5 scores of -0.75, -0.73 and -0.78 with mepolizumab versus placebo were observed in non-atopic, atopic and strongly atopic patients with blood eosinophil counts ≥300 cells/µL; consistent improvements in ACQ-5 were not observed in patients with blood eosinophil counts <150 or ≥150-300 cells/μL. Reductions in clinically significant exacerbations with mepolizumab versus placebo were also observed irrespective of sensitivity to HDMs.ConclusionMepolizumab was associated with a trend for reductions in clinically significant exacerbations and improved asthma control versus placebo in patients with severe eosinophilic asthma, irrespective of atopic status or HDM sensitivity.
| S-EPMC8214022 | biostudies-literature
Project description:IntroductionTargeted therapies for sepsis have failed to show benefit due to high variability among subjects. We sought to demonstrate different phenotypes of septic shock based solely on clinical features and show that these relate to outcome.MethodsA retrospective analysis was performed of a 1,023-subject cohort with early septic shock from the ProCESS trial. Twenty-three clinical variables at baseline were analyzed using hierarchical clustering, with consensus clustering used to identify and validate the ideal number of clusters in a derivation cohort of 642 subjects from 20 hospitals. Clusters were visualized using heatmaps over 0, 6, 24, and 72 h. Clinical outcomes were 14-day all-cause mortality and organ failure pattern. Cluster robustness was confirmed in a validation cohort of 381 subjects from 11 hospitals.ResultsFive phenotypes were identified, each with unique organ failure patterns that persisted in time. By enrollment criteria, all patients had shock. The two high-risk phenotypes were characterized by distinct multi-organ failure patterns and cytokine signatures, with the highest mortality group characterized most notably by liver dysfunction and coagulopathy while the other group exhibited primarily respiratory failure, neurologic dysfunction, and renal dysfunction. The moderate risk phenotype was that of respiratory failure, while low-risk phenotypes did not have a high degree of additional organ failure.ConclusionsSepsis phenotypes with distinct biochemical abnormalities may be identified by clinical characteristics alone and likely provide an opportunity for early clinical actionability and prognosis.
| S-EPMC9160971 | biostudies-literature